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Dos Reis DB, Linhares EPM, Dos Santos E Silva G, do Carmo Ferreira FH, Costa LAS, Ávila EP, de Almeida MV, de Souza MVN, da Silva Lourenço MC, Saraiva MF. Synthesis, Antituberculosis Evaluation and Structure-Activity Relationships of New SQ109 Analogs. Arch Pharm (Weinheim) 2025; 358:e3130. [PMID: 40235339 DOI: 10.1002/ardp.202400665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 02/14/2025] [Accepted: 03/27/2025] [Indexed: 04/17/2025]
Abstract
Tuberculosis (TB) is a bacterial disease that poses significant challenges in its treatment. It requires prolonged use of high doses of medication, which can lead to various side effects. These side effects often contribute to low patient adherence to treatment, thereby increasing the risk of developing drug-resistant strains. The SQ109 is a second-generation agent developed from ethambutol that has been emerging as a promising TB agent. The functionalization of its skeleton appears as a strategy to improve the physicochemical and biological properties. Hence, we report the synthesis of functionalized SQ109 scaffolds, the in vitro evaluation against Mycobacterium tuberculosis H37Rv strains, molecular docking simulations, and molecular dynamics of the interactions with the target membrane protein.
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Affiliation(s)
- Dijovani Batista Dos Reis
- LaSIMBio-Laboratório de Síntese de Moléculas Bioativas, Institute of Physics and Chemistry, Federal University of Itajubá, Itajubá, Brazil
| | - Emily Pacelli Moreira Linhares
- LaSIMBio-Laboratório de Síntese de Moléculas Bioativas, Institute of Physics and Chemistry, Federal University of Itajubá, Itajubá, Brazil
| | - Gabriel Dos Santos E Silva
- LaSIMBio-Laboratório de Síntese de Moléculas Bioativas, Institute of Physics and Chemistry, Federal University of Itajubá, Itajubá, Brazil
| | | | - Luiz Antônio Sodré Costa
- NEQC-Núcleo de Estudos em Química Computacional, Federal University of Juiz de Fora, Juiz de Fora, Brazil
| | - Eloah Pereira Ávila
- Chemistry Department, Institute of Exact Sciences, Federal University of Juiz de Fora, Juiz de Fora, Brazil
| | - Mauro Vieira de Almeida
- Chemistry Department, Institute of Exact Sciences, Federal University of Juiz de Fora, Juiz de Fora, Brazil
| | | | | | - Mauricio Frota Saraiva
- LaSIMBio-Laboratório de Síntese de Moléculas Bioativas, Institute of Physics and Chemistry, Federal University of Itajubá, Itajubá, Brazil
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Rai A, Jha NS. Targeting Mycobacterium tuberculosis Parallel G-Quadruplex Motifs with Aminoglycosides Neomycin and Streptomycin: Spectroscopic and Calorimetric Aspects. J Phys Chem B 2025; 129:1715-1727. [PMID: 39902947 DOI: 10.1021/acs.jpcb.4c06795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
Mycobacterium tuberculosis (Mtb) contains potential G-quadruplex (PGQ) motifs in the genes espK and cyp51, which are crucial for the bacteria's virulence within host cells. Aminoglycoside molecules are commonly used as antibiotics for ribosomal targets. This study provides insight into the interactions between these aminoglycosides and Mtb-PGQ sequences (espK and cyp51), shedding light on the structural and thermodynamic dynamics of their binding. This study demonstrates the stability, affinity, and conformation of Mtb-PGQ in the presence of neomycin and streptomycin. Ultraviolet-visible spectroscopy (UV-vis), circular dichroism spectroscopy (CD), CD thermal melting, isothermal titration calorimetry (ITC), and fluorescence intercalator displacement (FID) assays were used to comprehensively examine these interactions. Our results reveal that neomycin with Mtb-PGQexhibits hypochromism accompanied by a 4-5 nm red shift in the UV-visible absorption titration, whereas streptomycin exhibits a hypochromic shift without changes in the maximum wavelength. Notably, neomycin shows a nonlinear binding isotherm, suggesting the involvement of more than one binding process in the formation of neomycin.Mtb-PGQ complexes. Scatchard plot analysis indicates higher binding affinity values for neomycin compared with weaker affinity of streptomycin. CD studies reveal that neomycin decreases the ellipticity of Mtb-PGQ with a red shift while retaining the parallel topology, ultimately enhancing the thermal stability of both espK and cyp51. In contrast, streptomycin destabilizes the cells. ITC analysis reveals that neomycin exhibits the strongest binding affinity for cyp51, with the relative order being NEO-cyp51 > NEO-espk > STR-cyp51 > STR-espk. Moreover, thermodynamic analysis reveals that neomycin possesses a unique dual mode of binding through grooves as well as stacking. FID studies further confirm a lower DC50 value for neomycin than for streptomycin, suggesting that neomycin is a strong displacer of thiazole orange. Thus, the results show that neomycin with amino groups selectively recognizes the grooves of cyp51 over espK.
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Affiliation(s)
- Anupama Rai
- Department of Chemistry, National Institute of Technology, Patna 800005, India
| | - Niki S Jha
- Department of Chemistry, National Institute of Technology, Patna 800005, India
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Ullah H, Hassan SHA, Yang Q, Salama ES, Liu P, Li X. Dynamic interaction of antibiotic resistance between plant microbiome and organic fertilizers: sources, dissemination, and health risks. World J Microbiol Biotechnol 2024; 41:4. [PMID: 39690351 DOI: 10.1007/s11274-024-04214-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 11/24/2024] [Indexed: 12/19/2024]
Abstract
Antibiotic resistance is a global health problem driven by the irrational use of antibiotics in different areas (such as agriculture, animal farming, and human healthcare). Sub-lethal concentrations of antibiotic residues impose selective pressure on environmental, plant-associated, and human microbiome leading to the emergence of antibiotic-resistant bacteria (ARB). This review summarizes all sources of antibiotic resistance in agricultural soils (including manure, sewage sludge, wastewater, hospitals/pharmaceutical industry, and bioinoculants). The factors (such as the physicochemical properties of soil, root exudates, concentration of antibiotic exposure, and heavy metals) that facilitate the transmission of resistance in plant microbiomes are discussed. Potential solutions for effective measures and control of antibiotic resistance in the environment are also hypothesized. Manure exhibits the highest antibiotics load, followed by hospital and municipal WW. Chlortetracycline, tetracycline, and sulfadiazine have the highest concentrations in the manure. Antibiotic resistance from organic fertilizers is transmitted to the plant microbiome via horizontal gene transfer (HGT). Plant microbiomes serve as transmission routes of ARB and ARGS to humans. The ingestion of ARB leads to human health risks (such as ineffectiveness of medication, increased morbidity, and mortality).
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Affiliation(s)
- Habib Ullah
- Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China
| | - Sedky H A Hassan
- Department of Biology, College of Science, Sultan Qaboos University, Muscat 123, Muscat, Oman
| | - Qi Yang
- Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China
| | - El-Sayed Salama
- Department of Occupational and Environmental Health, School of Public Health, Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China.
| | - Pu Liu
- Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China.
| | - Xiangkai Li
- Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China
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de Lima Menezes G, Sales Bezerra K, Nobre Oliveira JI, Fontenele Araújo J, Soares Galvão D, Alves da Silva R, Vogel Saivish M, Laino Fulco U. Quantum mechanics insights into melatonin and analogs binding to melatonin MT 1 and MT 2 receptors. Sci Rep 2024; 14:10922. [PMID: 38740789 PMCID: PMC11091226 DOI: 10.1038/s41598-024-59786-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 04/15/2024] [Indexed: 05/16/2024] Open
Abstract
Melatonin receptors MT1 and MT2 are G protein-coupled receptors that mediate the effects of melatonin, a hormone involved in circadian rhythms and other physiological functions. Understanding the molecular interactions between these receptors and their ligands is crucial for developing novel therapeutic agents. In this study, we used molecular docking, molecular dynamics simulations, and quantum mechanics calculation to investigate the binding modes and affinities of three ligands: melatonin (MLT), ramelteon (RMT), and 2-phenylmelatonin (2-PMT) with both receptors. Based on the results, we identified key amino acids that contributed to the receptor-ligand interactions, such as Gln181/194, Phe179/192, and Asn162/175, which are conserved in both receptors. Additionally, we described new meaningful interactions with Gly108/Gly121, Val111/Val124, and Val191/Val204. Our results provide insights into receptor-ligand recognition's structural and energetic determinants and suggest potential strategies for designing more optimized molecules. This study enhances our understanding of receptor-ligand interactions and offers implications for future drug development.
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Affiliation(s)
- Gabriela de Lima Menezes
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande no Norte, Natal, RN, 59072-970, Brazil
- Bioinformatics Multidisciplinary Environment, Programa de Pós Graduação em Bioinformática, Universidade Federal do Rio Grande do Norte, Natal, RN, 59078-400, Brazil
| | - Katyanna Sales Bezerra
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande no Norte, Natal, RN, 59072-970, Brazil
- Applied Physics Department, University of Campinas, Campinas, São Paulo, 13083-859, Brazil
| | - Jonas Ivan Nobre Oliveira
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande no Norte, Natal, RN, 59072-970, Brazil
| | - John Fontenele Araújo
- Departamento de Fisiologia e Comportamento, Universidade Federal do Rio Grande no Norte, Natal, RN, 59072-970, Brazil
| | - Douglas Soares Galvão
- Applied Physics Department, University of Campinas, Campinas, São Paulo, 13083-859, Brazil
| | - Roosevelt Alves da Silva
- Unidade Especial de Ciências Exatas, Universidade Federal de Jataí, Jataí, GO, 75801-615, Brazil
| | - Marielena Vogel Saivish
- Laboratório de Pesquisas em Virologia, Departamento de Doenças Dermatológicas, Infecciosas e Parasitárias, Faculdade de Medicina de São José Do Rio Preto, São José Do Rio, Preto, SP, 15090-000, Brazil
- Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Brazilian Biosciences National Laboratory, Campinas, SP, 13083-100, Brazil
| | - Umberto Laino Fulco
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande no Norte, Natal, RN, 59072-970, Brazil.
- Bioinformatics Multidisciplinary Environment, Programa de Pós Graduação em Bioinformática, Universidade Federal do Rio Grande do Norte, Natal, RN, 59078-400, Brazil.
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de Carvalho Matias EG, Bezerra KS, Costa AHL, Clemente Junior WS, Oliveira JIN, Ribeiro Junior LA, Galvão DS, Fulco UL. Quantum biochemical analysis of the TtgR regulator and effectors. Sci Rep 2024; 14:8519. [PMID: 38609407 PMCID: PMC11015042 DOI: 10.1038/s41598-024-58441-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
The recent expansion of multidrug-resistant (MDR) pathogens poses significant challenges in treating healthcare-associated infections. Although antibacterial resistance occurs by numerous mechanisms, active efflux of the drugs is a critical concern. A single species of efflux pump can produce a simultaneous resistance to several drugs. One of the best-studied efflux pumps is the TtgABC: a tripartite resistance-nodulation-division (RND) efflux pump implicated in the intrinsic antibiotic resistance in Pseudomonas putida DOT-T1E. The expression of the TtgABC gene is down-regulated by the HTH-type transcriptional repressor TtgR. In this context, by employing quantum chemistry methods based on the Density Functional Theory (DFT) within the Molecular Fragmentation with Conjugate Caps (MFCC) approach, we investigate the coupling profiles of the transcriptional regulator TtgR in complex with quercetin (QUE), a natural polyphenolic flavonoid, tetracycline (TAC), and chloramphenicol (CLM), two broad-spectrum antimicrobial agents. Our quantum biochemical computational results show the: [i] convergence radius, [ii] total binding energy, [iii] relevance (energetically) of the ligands regions, and [iv] most relevant amino acids residues of the TtgR-QUE/TAC/CLM complexes, pointing out distinctions and similarities among them. These findings improve the understanding of the binding mechanism of effectors and facilitate the development of new chemicals targeting TtgR, helping in the battle against the rise of resistance to antimicrobial drugs. These advances are crucial in the ongoing fight against rising antimicrobial drug resistance, providing hope for a future where healthcare-associated infections can be more beneficially treated.
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Affiliation(s)
- E G de Carvalho Matias
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, Natal, RN, 59072-970, Brazil
| | - K S Bezerra
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, Natal, RN, 59072-970, Brazil
| | - A H Lima Costa
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, Natal, RN, 59072-970, Brazil
| | - W S Clemente Junior
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, Natal, RN, 59072-970, Brazil
| | - J I N Oliveira
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, Natal, RN, 59072-970, Brazil
| | - L A Ribeiro Junior
- Institute of Physics, University of Brasília, Brasília, 70919-970, Brazil.
| | - D S Galvão
- Applied Physics Department, University of Campinas, Campinas, São Paulo, Brazil
| | - U L Fulco
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, Natal, RN, 59072-970, Brazil
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da Rocha JM, Campos DMDO, Esmaile SC, Menezes GDL, Bezerra KS, da Silva RA, Junior EDDS, Tayyeb JZ, Akash S, Fulco UL, Alqahtani T, Oliveira JIN. Quantum biochemical analysis of the binding interactions between a potential inhibitory drug and the Ebola viral glycoprotein. J Biomol Struct Dyn 2024:1-17. [PMID: 38258414 DOI: 10.1080/07391102.2024.2305314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 01/08/2024] [Indexed: 01/24/2024]
Abstract
Ebola virus disease (EVD) causes outbreaks and epidemics in West Africa that persist until today. The envelope glycoprotein of Ebola virus (GP) consists of two subunits, GP1 and GP2, and plays a key role in anchoring or fusing the virus to the host cell in its active form on the virion surface. Toremifene (TOR) is a ligand that mainly acts as an estrogen receptor antagonist; however, a recent study showed a strong and efficient interaction with GP. In this context, we aimed to evaluate the energetic affinity features involved in the interaction between GP and toremifene by computer simulation techniques using the Molecular Fractionation Method with Conjugate Caps (MFCC) scheme and quantum-mechanical (QM) calculations, as well as missense mutations to assess protein stability. We identified ASP522, GLU100, TYR517, THR519, LEU186, LEU515 as the most attractive residues in the EBOV glycoprotein structure that form the binding pocket. We divided toremifene into three regions and evaluated that region i was more important than region iii and region ii for the formation of the TOR-GP1/GP2 complex, which might control the molecular remodeling process of TOR. The mutations that caused more destabilization were ARG134, LEU515, TYR517 and ARG559, while those that caused stabilization were GLU523 and ASP522. TYR517 is a critical residue for the binding of TOR, and is highly conserved among EBOV species. Our results may help to elucidate the mechanism of drug action on the GP protein of the Ebola virus and subsequently develop new pharmacological approaches against EVD.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Jaerdyson M da Rocha
- Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Daniel M de O Campos
- Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Stephany C Esmaile
- Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Gabriela de L Menezes
- Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Katyanna S Bezerra
- Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Roosevelt A da Silva
- Core Collaboratives of BioSistemas, Special Unit of Exact Sciences, Federal University of Jataí, Jataí, GO, Brazil
| | - Edilson D da S Junior
- Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Jehad Zuhair Tayyeb
- Department of Clinical Biochemistry, College of Medicine, University of Jeddah, Jeddah, Saudi Arabia
| | - Shopnil Akash
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Birulia, Ashulia, Dhaka, Bangladesh
| | - Umberto L Fulco
- Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Taha Alqahtani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Jonas I N Oliveira
- Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, Natal, RN, Brazil
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Mandova T, Saivish MV, Menezes GDL, Bezerra KS, Fulco UL, da Silva RA, Da Costa FB, Nogueira ML. Antiviral Activity and Molecular Dynamics Simulation of Hops Compounds against Oropouche Virus ( Peribunyaviridae). Pharmaceutics 2023; 15:2769. [PMID: 38140109 PMCID: PMC10747393 DOI: 10.3390/pharmaceutics15122769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/20/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023] Open
Abstract
The Oropouche virus (OROV) is a member of the family Peribunyaviridae (order Bunyavirales) and the cause of a dengue-like febrile illness transmitted mainly by biting midges and mosquitoes. In this study, we aimed to explore acylphloroglucinols and xanthohumol from hops (Humulus lupulus L.) as a promising alternative for antiviral therapies. The evaluation of the inhibitory potential of hops compounds on the viral cycle of OROV was performed through two complementary approaches. The first approach applies cell-based assay post-inoculation experiments to explore the inhibitory potential on the latest steps of the viral cycle, such as genome translation, replication, virion assembly, and virion release from the cells. The second part covers in silico methods evaluating the ability of those compounds to inhibit the activity of the endonuclease domain, which is essential for transcription, binding, and cleaving RNA. In conclusion, the beta acids showed strongest inhibitory potential in post-treatment assay (EC50 = 26.7 µg/mL). Xanthohumol had the highest affinity for OROV endonuclease followed by colupulone and cohumulone. This result contrasts with that observed for docking and MM/PBSA analysis, where cohumulone was found to have a higher affinity. Finally, among the three tested ligands, Lys92 and Arg33 exhibited the highest affinity with the protein.
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Affiliation(s)
- Tsvetelina Mandova
- AsterBioChem Research Team, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-020, SP, Brazil
- Gilson Purification, 22 rue Bourseul, 56890 Saint Avé, France
| | - Marielena Vogel Saivish
- Laboratórios de Pesquisas em Virologia, Departamento de Doenças Dermatológicas, Infecciosas e Parasitárias, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto 15090-000, SP, Brazil; (M.V.S.)
- Brazilian Biosciences National Laboratory, Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas 13083-100, SP, Brazil
| | - Gabriela de Lima Menezes
- Bioinformatics Multidisciplinary Environment, Programa de Pós Graduação em Bioinformática, Universidade Federal do Rio Grande do Norte, Natal 59078-400, RN, Brazil; (G.d.L.M.); (U.L.F.)
| | - Katyanna Sales Bezerra
- Bioinformatics Multidisciplinary Environment, Programa de Pós Graduação em Bioinformática, Universidade Federal do Rio Grande do Norte, Natal 59078-400, RN, Brazil; (G.d.L.M.); (U.L.F.)
| | - Umberto Laino Fulco
- Bioinformatics Multidisciplinary Environment, Programa de Pós Graduação em Bioinformática, Universidade Federal do Rio Grande do Norte, Natal 59078-400, RN, Brazil; (G.d.L.M.); (U.L.F.)
| | | | - Fernando Batista Da Costa
- AsterBioChem Research Team, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-020, SP, Brazil
| | - Maurício Lacerda Nogueira
- Laboratórios de Pesquisas em Virologia, Departamento de Doenças Dermatológicas, Infecciosas e Parasitárias, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto 15090-000, SP, Brazil; (M.V.S.)
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
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Lima Costa AH, Bezerra KS, de Lima Neto JX, Oliveira JIN, Galvão DS, Fulco UL. Deciphering Interactions between Potential Inhibitors and the Plasmodium falciparum DHODH Enzyme: A Computational Perspective. J Phys Chem B 2023; 127:9461-9475. [PMID: 37897437 DOI: 10.1021/acs.jpcb.3c05738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/30/2023]
Abstract
Malaria is a parasitic disease that, in its most severe form, can even lead to death. Insect-resistant vectors, insufficiently effective vaccines, and drugs that cannot stop parasitic infestations are making the fight against the disease increasingly difficult. It is known that the enzyme dihydroorotate dehydrogenase (DHODH) is of paramount importance for the synthesis of pyrimidine from the Plasmodium precursor, that is, for its growth and reproduction. Therefore, its blockade can lead to disruption of the parasite's life cycle in the vertebrate host. In this scenario, PfDHODH inhibitors have been considered candidates for a new therapy to stop the parasitic energy source. Given what is known, in this work, we applied molecular fractionation with conjugated caps (MFCC) in the framework of the quantum formalism of density functional theory (DFT) to evaluate the energies of the interactions between the enzyme and the different triazolopyrimidines (DSM483, DMS557, and DSM1), including a complex carrying the mutation C276F. From these results, it was possible to identify the main features of each system, focusing on the wild-type and mutant PfDHODH and examining the major amino acid residues that are part of the four complexes. Our analysis provides new information that can be used to develop new drugs that could prove to be more effective alternatives to present antimalarial drugs.
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Affiliation(s)
- Aranthya Hevelly Lima Costa
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970 Natal-RN, Brazil
| | - Katyanna Sales Bezerra
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970 Natal-RN, Brazil
- Applied Physics Department, University of Campinas, 130838-59 Campinas, São Paulo, Brazil
| | - José Xavier de Lima Neto
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970 Natal-RN, Brazil
| | - Jonas Ivan Nobre Oliveira
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970 Natal-RN, Brazil
| | - Douglas Soares Galvão
- Applied Physics Department, University of Campinas, 130838-59 Campinas, São Paulo, Brazil
| | - Umberto Laino Fulco
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970 Natal-RN, Brazil
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Herrera CK, Vahdani A, Yang C, Bates M, Lunt SY, Borhan B, Lunt RR. Enhanced Lifetime of Cyanine Salts in Dilute Matrix Luminescent Solar Concentrators via Counterion Tuning. ACS PHOTONICS 2023; 10:3195-3202. [PMID: 39071812 PMCID: PMC11281435 DOI: 10.1021/acsphotonics.3c00602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Organic luminophores offer great potential for energy harvesting and light emission due to tunable spectral properties, strong luminescence, high solubility, and excellent wavelength-selectivity. To realize their full potential, the lifetimes of luminophores must extend to many years under illumination. Many organic luminophores, however, have a tendency to degrade and undergo rapid photobleaching, leading to the perception of intrinsic instability of organic molecules. In this work we demonstrate that by exchanging the counterion of a heptamethine cyanine salt the photostability and corresponding lifetime of dilute cyanine salts can be enhanced by orders of magnitude from 10 hours to an extrapolated lifetime of greater than 65,000 hours under illumination. To help correlate and comprehend the underlying mechanism behind this phenomenon, the water contact angle and binding energy of each pairing were measured and calculated. We find that increased water contact angle, and therefore increasing hydrophobicity, generally correlate to improved lifetimes. Similarly, a lower absolute binding energy between cation and anion correlates to increased lifetimes. Utilizing the binding energy formalism, we predict the stability of a new anion and experimentally verify with good consistency. Moving forward, these factors could be used to rapidly screen and identify highly photostable organic luminophore salt systems for a range of energy harvesting and light emitting applications.
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Affiliation(s)
- Christopher K. Herrera
- Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan 48824, United States
| | - Aria Vahdani
- Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
| | - Chenchen Yang
- Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan 48824, United States
| | - Matthew Bates
- Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan 48824, United States
| | - Sophia Y. Lunt
- Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan 48824, United States
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, United States
| | - Babak Borhan
- Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
| | - Richard R. Lunt
- Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan 48824, United States
- Department of Physics and Astronomy, Michigan State University, East Lansing, Michigan 48824, United States
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Rollo RF, Mori G, Hill TA, Hillemann D, Niemann S, Homolka S, Fairlie DP, Blumenthal A. Wollamide Cyclic Hexapeptides Synergize with Established and New Tuberculosis Antibiotics in Targeting Mycobacterium tuberculosis. Microbiol Spectr 2023; 11:e0046523. [PMID: 37289062 PMCID: PMC10433873 DOI: 10.1128/spectrum.00465-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 05/11/2023] [Indexed: 06/09/2023] Open
Abstract
Shorter and more effective treatment regimens as well as new drugs are urgent priorities for reducing the immense global burden of tuberculosis (TB). As treatment of TB currently requires multiple antibiotics with diverse mechanisms of action, any new drug lead requires assessment of potential interactions with existing TB antibiotics. We previously described the discovery of wollamides, a new class of Streptomyces-derived cyclic hexapeptides with antimycobacterial activity. To further assess the value of the wollamide pharmacophore as an antimycobacterial lead, we determined wollamide interactions with first- and second-line TB antibiotics by determining fractional inhibitory combination index and zero interaction potency scores. In vitro two-way and multiway interaction analyses revealed that wollamide B1 synergizes with ethambutol, pretomanid, delamanid, and para-aminosalicylic acid in inhibiting the replication and promoting the killing of phylogenetically diverse clinical and reference strains of the Mycobacterium tuberculosis complex (MTBC). Wollamide B1 antimycobacterial activity was not compromised in multi- and extensively drug-resistant MTBC strains. Moreover, growth-inhibitory antimycobacterial activity of the combination of bedaquiline/pretomanid/linezolid was further enhanced by wollamide B1, and wollamide B1 did not compromise the antimycobacterial activity of the isoniazid/rifampicin/ethambutol combination. Collectively, these findings add new dimensions to the desirable characteristics of the wollamide pharmacophore as an antimycobacterial lead compound. IMPORTANCE Tuberculosis (TB) is an infectious disease that affects millions of people globally, with 1.6 million deaths annually. TB treatment requires combinations of multiple different antibiotics for many months, and toxic side effects can occur. Therefore, shorter, safer, more effective TB therapies are required, and these should ideally also be effective against drug-resistant strains of the bacteria that cause TB. This study shows that wollamide B1, a chemically optimized member of a new class of antibacterial compounds, inhibits the growth of drug-sensitive as well as multidrug-resistant Mycobacterium tuberculosis isolated from TB patients. In combination with TB antibiotics, wollamide B1 synergistically enhances the activity of several antibiotics, including complex drug combinations that are currently used for TB treatment. These new insights expand the catalogue of the desirable characteristics of wollamide B1 as an antimycobacterial lead compound that might inspire the development of improved TB treatments.
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Affiliation(s)
- Rachel F. Rollo
- Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia
| | - Giorgia Mori
- Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia
| | - Timothy A. Hill
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Doris Hillemann
- National and WHO Supranational Reference Center for Mycobacteria, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
| | - Stefan Niemann
- Molecular and Experimental Mycobacteriology, Priority Area Infections, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany
| | - Susanne Homolka
- Molecular and Experimental Mycobacteriology, Priority Area Infections, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
| | - David P. Fairlie
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Antje Blumenthal
- Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia
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11
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Leowattana W, Leowattana P, Leowattana T. Tuberculosis of the spine. World J Orthop 2023; 14:275-293. [PMID: 37304201 PMCID: PMC10251269 DOI: 10.5312/wjo.v14.i5.275] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/24/2023] [Accepted: 04/12/2023] [Indexed: 05/18/2023] Open
Abstract
Pott's spine, commonly known as spinal tuberculosis (TB), is an extrapulmonary form of TB caused by Mycobacterium TB. Pott's paraplegia occurs when the spine is involved. Spinal TB is usually caused by the hematogenous spread of infection from a central focus, which can be in the lungs or another location. Spinal TB is distinguished by intervertebral disc involvement caused by the same segmental arterial supply, which can result in severe morbidity even after years of approved therapy. Neurological impairments and spine deformities are caused by progressive damage to the anterior vertebral body. The clinical, radiographic, microbiological, and histological data are used to make the diagnosis of spinal TB. In Pott's spine, combination multidrug antitubercular therapy is the basis of treatment. The recent appearance of multidrug-resistant/extremely drug-resistant TB and the growth of human immunodeficiency virus infection have presented significant challenges in the battle against TB infection. Patients who come with significant kyphosis or neurological impairments are the only ones who require surgical care. Debridement, fusion stabilization, and correction of spinal deformity are the cornerstones of surgical treatment. Clinical results for the treatment of spinal TB are generally quite good with adequate and prompt care.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Pathomthep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakarinwirot University, Wattana 10110, Bangkok, Thailand
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12
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Rayshan AM, Al-Rawi ZH, A. Odhar H. Introducing Larger plate and Optimum Distribution Pattern in Microbiological assay. RESEARCH JOURNAL OF PHARMACY AND TECHNOLOGY 2023:294-300. [DOI: 10.52711/0974-360x.2023.00053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
First, clinical sample antibiotic assay process. 1966, Appl. Microbiol. 14:2:170–177. This modified agar-disks diffusion experiment employs big glass plates to enable 81 replications per plate. With an agar punch, more than agar disks may be made fast. The savings in zone of inhibition (zoi) from high repeated concentrations of diverse antibiotics with big plates and agar-disks makes it economically possible to employ pooled any antibiotic concentrate. Methods for creating disk diffusion agar and inhibiting bacterial susceptibility degradation are provided. Preparing and maintaining assay organisms is described. Instead of diluting antibiotic tablets to a small range at various concentrations to spread the agar well, they are tested immediately to avoid contamination at the tested concentrations. This is conceivable owing to antibiotic mobility (dilution) and curvilinear computations between area and antibiotic concentrations. This approach has been adapted to many antibiotics. With this technology, vast numbers of antibiotic disks may be tested quickly and accurately. Solid media can be used for antimicrobial susceptibility testing. Solids tests are straightforward and affordable, but they aren't quantitative. Antimicrobial agent diffusion may impair the accuracy of plate-based tests. After applying the above, we evaluated this assumption using the "Eight Queens Puzzle Model" of antibiotic dispersion and a disc diffusion test to estimate the connection between agar depth and area of inhibition and to determine the ideal agar depth. Our studies with agar-diffusion in plates and agar thickness demonstrated that this model describes antibiotic zoi sizes accurately. However, linear regression to explain the link between agar thickness and growth inhibition zone for Staphylococcus aureus and Escherichia coli treated with various antibiotic discs, three groups, the first group (erythromycin) emerged-zone equal sizes for both bacteria. Both bacteria were susceptible to gentamicin and ceftriaxone. Ciprofloxacin's three-group model fit best. Streptomycin's residual deviation was the same for both bacteria. The concentration dependency in the streptomycin group was greater than linear, which may imply a range of low susceptibility rather than a single cut-off dose.
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Affiliation(s)
- Ali M. Rayshan
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Zuhair H. Al-Rawi
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Hasanain A. Odhar
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
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13
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Campos DMDO, Silva MKD, Barbosa ED, Leow CY, Fulco UL, Oliveira JIN. Exploiting reverse vaccinology approach for the design of a multiepitope subunit vaccine against the major SARS-CoV-2 variants. Comput Biol Chem 2022; 101:107754. [PMID: 36037724 PMCID: PMC9385604 DOI: 10.1016/j.compbiolchem.2022.107754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/29/2022] [Accepted: 08/09/2022] [Indexed: 11/03/2022]
Abstract
The current COVID-19 pandemic, an infectious disease caused by the novel coronavirus (SARS-CoV-2), poses a threat to global health because of its high rate of spread and death. Currently, vaccination is the most effective method to prevent the spread of this disease. In the present study, we developed a novel multiepitope vaccine against SARS-CoV-2 containing Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (BA.1) variants. To this end, we performed a robust immunoinformatics approach based on multiple epitopes of the four structural proteins of SARS-CoV-2 (S, M, N, and E) from 475 SARS-CoV-2 genomes sequenced from the regions with the highest number of registered cases, namely the United States, India, Brazil, France, Germany, and the United Kingdom. To investigate the best immunogenic epitopes for linear B cells, cytotoxic T lymphocytes (CTL), and helper T lymphocytes (HTL), we evaluated antigenicity, allergenicity, conservation, immunogenicity, toxicity, human population coverage, IFN-inducing, post-translational modifications, and physicochemical properties. The tertiary structure of a vaccine prototype was predicted, refined, and validated. Through docking experiments, we evaluated its molecular coupling to the key immune receptor Toll-Like Receptor 3 (TLR3). To improve the quality of docking calculations, quantum mechanics/molecular mechanics calculations (QM/MM) were used, with the QM part of the simulations performed using the density functional theory formalism (DFT). Cloning and codon optimization were performed for the successful expression of the vaccine in E. coli. Finally, we investigated the immunogenic properties and immune response of our SARS-CoV-2 multiepitope vaccine. The results of the simulations show that administering our prototype three times significantly increases the antibody response and decreases the amount of antigens. The proposed vaccine candidate should therefore be tested in clinical trials for its efficacy in neutralizing SARS-CoV-2.
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Affiliation(s)
- Daniel Melo de Oliveira Campos
- Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, 59064-741, Natal/RN, Brazil.
| | - Maria Karolaynne da Silva
- Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, 59064-741, Natal/RN, Brazil.
| | - Emmanuel Duarte Barbosa
- Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, 59064-741, Natal/RN, Brazil.
| | | | - Umberto Laino Fulco
- Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, 59064-741, Natal/RN, Brazil.
| | - Jonas Ivan Nobre Oliveira
- Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, 59064-741, Natal/RN, Brazil.
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14
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Evaluation of Susceptibility of the Human Pathogen Helicobacter pylori to the Antibiotic Capreomycin. ScientificWorldJournal 2022; 2022:8924023. [PMID: 35958801 PMCID: PMC9357814 DOI: 10.1155/2022/8924023] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/20/2022] [Accepted: 06/21/2022] [Indexed: 11/23/2022] Open
Abstract
Helicobacter pylori infection causes gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma, and gastric cancer and can also promote thrombosis. It is estimated that approximately 4.5 billion individuals are infected, thus rendering H. pylori the most prevalent microbial pathogen. Currently established regimes for antibiotic treatment are massively challenged by increasing drug resistance and the development of novel antimicrobial therapies is urgently required. The antibiotic capreomycin is clinically used against multiple drug-resistant strains of Mycobacterium tuberculosis. It targets the complex between TlyA, a hemolysin- and RNA-binding protein, and the bacterial rRNA. In this study we have explored the possible antibacterial effects of capreomycin against several strains of H. pylori and found only moderate activity which was comparable to metronidazole-resistant strains. Molecular docking of capreomycin to TlyA proteins from H. pylori and M. tuberculosis identified several residues within TlyA which interact with the drug; however, binding affinities of H. pylori– TlyA for capreomycin appear to be higher than those of Mycobacterium– TlyA. The data suggest that capreomycin may warrant further investigations into its potential use as antibiotic against H. pylori.
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15
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Clara TH, Prasana JC, Prabhu N, Rizwana BF. Spectroscopic profiling and molecular docking of novel chalcone derivative (2E)-1-(3,4-dimethoxyphenyl)-3-(4-n-propyloxyphenyl)-2-propen-1-one- A prospective respiratory drug. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2021.132138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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16
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Jia H, Chu H, Dai G, Cao T, Sun Z. Rv1258c acts as a drug efflux pump and growth controlling factor in Mycobacterium tuberculosis. Tuberculosis (Edinb) 2022; 133:102172. [PMID: 35158297 DOI: 10.1016/j.tube.2022.102172] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 01/17/2022] [Accepted: 01/23/2022] [Indexed: 11/27/2022]
Abstract
The possible role of efflux pump as a survival mechanism in Mycobacterium tuberculosis (M. tb) is gaining an increasing attention. Previously, Rv1258c (Tap) and its certain mutations confer the clinically relevant drug resistance. In this study, we found new mutations of Rv1258c in G195C, T297P and I328T. Effect of modulating T297P and I328T on the drug resistance by knockout and complement in M. tb H37Rv showed that M. tb ΔRv1258c showed a slightly lower MIC for rifampin, ethambutol, ofloxacin, amikacin, capreomycin and streptomycin than M. tb H37Rv WT and the complement. Rv1258c T297P and Rv1258c I328T showed an increased drug resistance to ethambutol and capreomycin than the complement of Rv1258c WT. Most importantly, M. tb ΔRv1258c exhibited a slow growth in the normal culture medium. TMT-based quantitative proteomics analysis of M. tb ΔRv1258c and WT showed that the knockout of Rv1258c greatly down-regulated the expression of the ribosome system and one of the special five type VII secretion systems, ESX-3, which impaired the bacterial growth. These results indicate that the newly found T297P and I328T mutations of Rv1258c contributed to an increased resistance to ethambutol and capreomycin, and Rv1258c as growth controlling factor influencing the growth of M. tb.
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Affiliation(s)
- Hongbing Jia
- Beijing Key Laboratory in Drug Resistant Tuberculosis Research, Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, China; Translational Medicine Center, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China
| | - Hongqian Chu
- Beijing Key Laboratory in Drug Resistant Tuberculosis Research, Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, China; Translational Medicine Center, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China
| | - Guangming Dai
- Beijing Key Laboratory in Drug Resistant Tuberculosis Research, Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, China; Translational Medicine Center, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China
| | - Tingming Cao
- Beijing Key Laboratory in Drug Resistant Tuberculosis Research, Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, China; Translational Medicine Center, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China
| | - Zhaogang Sun
- Beijing Key Laboratory in Drug Resistant Tuberculosis Research, Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, China; Translational Medicine Center, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China.
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17
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Tavares ABM, Albuquerque EL. A Quantum Chemistry Approach of Breast Cancer Drugs Bound to Human Serum Albumin. ADVANCED THEORY AND SIMULATIONS 2022. [DOI: 10.1002/adts.202100464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Ana Beatriz M.L.A. Tavares
- Departamento de Biofísica Universidade Federal do Rio Grande do Norte Natal‐RN 59072‐970 Brazil
- Hospital das Clínicas Universidade Federal de Pernambuco Recife‐PE 50.670‐901 Brazil
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18
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Santos JLS, Bezerra KS, Barbosa ED, Pereira ACL, Meurer YSR, Oliveira JIN, Gavioli EC, Fulco UL. In silico analysis of energy interactions between nociceptin/orfanin FQ receptor and two antagonists with potential antidepressive action. NEW J CHEM 2022. [DOI: 10.1039/d2nj00916a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
This study addresses the binding energies of NOPR-ligand complexes and presents the main amino acid residues involved in the interaction between these complexes.
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Affiliation(s)
- J. L. S. Santos
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil
| | - K. S. Bezerra
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil
| | - E. D. Barbosa
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil
| | - A. C. L. Pereira
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil
| | - Y. S. R. Meurer
- Departamento de Psicologia, Universidade Federal da Paraíba, 58051-900, João Pessoa-PB, Brazil
| | - J. I. N. Oliveira
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil
| | - E. C. Gavioli
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil
| | - U. L. Fulco
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil
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19
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Design, Synthesis and In Vitro Antimicrobial Activity of 6-(1H-Benzimidazol-2-yl)-3,5-dimethyl-4-oxo-2-thio-3,4-dihydrothieno[2,3-d]pyrimidines. Sci Pharm 2021. [DOI: 10.3390/scipharm89040049] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The rapid development in bacterial resistance to many groups of known antibiotics forces the researchers to discover antibacterial drug candidates with previously unknown mechanisms of action, one of the most relevant being the inhibition of tRNA (Guanine37-N1)-methyltransferase (TrmD). The discovery of selective TrmD inhibitors in the series of carboxamide derivatives of thienopyrimidines became a background for further modification of the similar structures aimed at the development of promising antibacterial agents. As part of this research, we carried out the construction of heterocyclic hybrids bearing the moieties of thieno[2,3-d]pyrimidine and benzimidazole starting from 3,5-dimethyl-4-oxo-2-thioxo-1H-thieno[2,3-d]pyrimidine-6-carboxylic acid, which was used as the pivotal intermediate. The hybrid molecule of 6-(1H-benzimidazol-2-yl)-3,5-dimethyl-2-thioxo-1H-thieno[2,3-d]pyrimidin-4-one prepared via condensation of the carboxylic acid with ortho-phenylenediamine was further alkylated with aryl/hetaryl chloroacetamides and benzyl chloride to produce the series of S-alkyl derivatives. The results of molecular docking studies for the obtained series of S-alkyl benzimidazole-thienopyrimidines showed their high affinity to the TrmD isolated from the P. aeruginosa. The results of antimicrobial activity screening revealed the antimicrobial properties for all of the studied molecules against both Gram-positive and Gram-negative bacteria and the Candida albicans fungal strain. The highest antimicrobial activity was determined for 2-{[6-(1H-benzimidazol-2-yl)-3,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl]thio}-N-(4-isopropylphenyl)acetamide, which also had the highest affinity to the TrmD inhibitor’s binding site according to the docking studies results.
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20
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Vianna JF, Bezerra KS, Lima Costa AH, Barbosa ED, Lima Neto JX, Oliveira JIN, Freire VN, Fulco UL. New ethionamide boosters and EthR2: structural and energetic analysis. Phys Chem Chem Phys 2021; 23:23233-23241. [PMID: 34623361 DOI: 10.1039/d1cp02853g] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Ethionamide (ETH) is a high-profile drug for the treatment of patients with multidrug-resistant Mycobacterium tuberculosis and, in order to produce its inhibitory effects, it needs to be bioactivated by monooxygenase EthA. This process is under the control of the transcriptional repressors EthR and EthR2, so that their inhibition results in the boosting of ethionamide activation. Herein, through crystallographic data and computer simulations, we calculated the interaction binding energies of four inhibitors with improved in vitro potency, namely BDM76060 (PDB ID: 6HS1), BDM72201 (PDB ID: 6HRX), BDM76150 (PDB ID: 6HS2) and BDM72719 (PDB ID: 6HRY), in complexes with the transcriptional repressor EthR2, using density functional theory (DFT) within the molecular fractionation with conjugated caps (MFCC) approach. It was observed that these ligands share the same binding site within a 10.0 Å radius of the EthR2 protein; however, their structural particularities have a significant impact on the global energies of systems. The BDM72201 and BDM72719 components are weakly attached to the binding site, while BDM76060 and BDM76150 components produce stronger bonds, corroborating with experimental studies demonstrating that BDM76060 and BDM76150 are more successful in producing inhibitory effects. BDM76060 and BDM76150 have many functional groups that increase the contact surface with the protein and attract a more significant number of amino acid residues, being able to produce polarities that generate stronger interactions. In the current scenario of a growing number of cases of bacterial resistance, the obtained data can be used to guide clinical trials of these inhibitors and other inhibitors that act on the alternative EthR2 pathway, focusing on improving the activity of ethionamide, its effectiveness, a reduction in the treatment time and exposure to cytotoxic effects.
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Affiliation(s)
- J F Vianna
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil.
| | - K S Bezerra
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil.
| | - A H Lima Costa
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil.
| | - E D Barbosa
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil.
| | - J X Lima Neto
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil.
| | - J I N Oliveira
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil.
| | - V N Freire
- Departamento de Física, Universidade Federal do Ceará, 60455-760, Fortaleza, CE, Brazil
| | - U L Fulco
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil.
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21
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Tavares ABMLA, Albuquerque EL. Quantum binding energies of checkpoint CTLA-4 in complex with the immuno-oncological drug ipilimumab. Phys Chem Chem Phys 2021; 23:15620-15627. [PMID: 34264254 DOI: 10.1039/d1cp01977e] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Inhibition of the checkpoint protein CTLA-4 by the US-FDA's approved monoclonal antibody ipilimumab has delivered breakthrough therapies against a wide range of cancers, being an important issue for clinical research. To date, many structural properties of this drug have been unveiled. However, the binding energy features of the receptor CTLA-4 in complex with its drug inhibitor, based on crystallographic data, need a deeper understanding. Within this context, by employing quantum chemistry we investigate in silico the binding energy features of the checkpoint protein CTLA-4 in complex with its drug inhibitor, highlighting the most relevant residue-residue interactions, looking for new insights into the mechanisms of pathway blockade to further engineer its affinity and selectivity. Our computational results not only give a better understanding of the binding mechanisms, but also point to an efficient alternative towards the development of antibody-based drugs, leading to new treatments for cancer therapy based upon immunotherapy.
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Affiliation(s)
- Ana Beatriz M L A Tavares
- Departamento de Bioquímica, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil. and Hospital das Clínicas, Universidade Federal de Pernambuco, 50.670-901, Recife-PE, Brazil
| | - E L Albuquerque
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil.
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22
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Pereira ACL, Bezerra KS, Santos JLS, I N Oliveira J, Freire VN, Fulco UL. In silico approach of modified melanoma peptides and their immunotherapeutic potential. Phys Chem Chem Phys 2021; 23:2836-2845. [PMID: 33470998 DOI: 10.1039/d0cp05322h] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Melanoma is a type of skin cancer with increasing incidence worldwide and high lethality. Conventional forms of treatment are not effective in advanced cancer stages. Hence, immunotherapeutic approaches have been tested to modulate immune response against tumor cells. Some vaccine models using tumor-associated antigens (TAAs) such as glycoprotein 100 (gp100) have been studied, but their expected effectiveness has not been shown until now. Antigen immunogenicity is a crucial point to improve the immune response, and therefore mutations are inserted in peptide sequences. It is possible to understand the interactions which occur between peptides and immune system molecules through computer simulation, and this is essential in order to guide efficient vaccine models. In this work, we have calculated the interaction binding energies of crystallographic data based on modified gp100 peptides and HLA-A*0201 using density functional theory (DFT) and the molecular fractionation with conjugated caps (MFCC) approach. Our results show the most relevant residue-residue interactions, the impact of three mutations in their binding sites, and the main HLA-A*0201 amino acids for peptide-HLA binding.
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Affiliation(s)
- A C L Pereira
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil.
| | - K S Bezerra
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil.
| | - J L S Santos
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil.
| | - J I N Oliveira
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil.
| | - V N Freire
- Departamento de Física, Universidade Federal do Ceará, 60455-760, Fortaleza-CE, Brazil
| | - U L Fulco
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil.
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23
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Esmaile SC, Bezerra KS, de Oliveira Campos DM, da Silva MK, Neto JXL, Manzoni V, Fulco UL, Oliveira JIN. Quantum binding energy features of the drug olmesartan bound to angiotensin type-1 receptors in the therapeutics of stroke. NEW J CHEM 2021. [DOI: 10.1039/d1nj03975j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
We investigated the binding energies of 105 residues within a 10 Å pocket radius, predicted the energetic relevance of olmesartan regions, and the influence of individual protein segments on OLM -AT1 binding.
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Affiliation(s)
- Stephany Campanelli Esmaile
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil
| | - Katyanna Sales Bezerra
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil
| | | | - Maria Karolaynne da Silva
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil
| | - José Xavier Lima Neto
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil
| | - Vinicius Manzoni
- Instituto de Física, Universidade Federal de Alagoas, 57072-970, Maceio, AL, Brazil
| | - Umberto Laino Fulco
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil
| | - Jonas Ivan Nobre Oliveira
- Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil
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24
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Li N, Zeng W, Xu S, Zhou J. Toward fine-tuned metabolic networks in industrial microorganisms. Synth Syst Biotechnol 2020; 5:81-91. [PMID: 32542205 PMCID: PMC7283098 DOI: 10.1016/j.synbio.2020.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 03/30/2020] [Accepted: 05/06/2020] [Indexed: 12/11/2022] Open
Abstract
There are numerous microorganisms in nature capable of synthesizing diverse useful compounds; however, these natural microorganisms are generally inefficient in the production of target products on an industrial scale, relative to either chemical synthesis or extraction methods. To achieve industrial production of useful compounds, these natural microorganisms must undergo a certain degree of mutation or effective fine-tuning strategies. This review describes how to achieve an ideal metabolic fine-tuned process, including static control strategies and dynamic control strategies. The static control strategies mainly focus on various matabolic engineering strategies, including protein engineering, upregulation/downregulation, and combinatrorial control of these metabolic engineering strategies, to enhance the flexibility of their application in fine-tuned metabolic metworks. Then, we focus on the dynamic control strategies for fine-tuned metabolic metworks. The design principles derived would guide us to construct microbial cell factories for various useful compounds.
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Affiliation(s)
- Ning Li
- Key Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, China.,National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, China.,Jiangsu Provisional Research Center for Bioactive Product Processing Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, China
| | - Weizhu Zeng
- Key Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, China.,National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, China.,Jiangsu Provisional Research Center for Bioactive Product Processing Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, China
| | - Sha Xu
- Key Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, China.,National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, China.,Jiangsu Provisional Research Center for Bioactive Product Processing Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, China
| | - Jingwen Zhou
- Key Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, China.,National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, China.,Jiangsu Provisional Research Center for Bioactive Product Processing Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, China
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25
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Campos DMO, Bezerra KS, Esmaile SC, Fulco UL, Albuquerque EL, Oliveira JIN. Intermolecular interactions of cn-716 and acyl-KR-aldehyde dipeptide inhibitors against Zika virus. Phys Chem Chem Phys 2020; 22:15683-15695. [DOI: 10.1039/d0cp02254c] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Structural representation and graphic panel showing the most relevant residues that contribute to the ZIKV NS2B–NS3–ligand complexes.
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Affiliation(s)
- Daniel M. O. Campos
- Departamento de Biofísica e Farmacologia
- Universidade Federal do Rio Grande do Norte
- Natal
- Brazil
| | - Katyanna S. Bezerra
- Departamento de Biofísica e Farmacologia
- Universidade Federal do Rio Grande do Norte
- Natal
- Brazil
| | - Stephany C. Esmaile
- Departamento de Biofísica e Farmacologia
- Universidade Federal do Rio Grande do Norte
- Natal
- Brazil
| | - Umberto L. Fulco
- Departamento de Biofísica e Farmacologia
- Universidade Federal do Rio Grande do Norte
- Natal
- Brazil
| | | | - Jonas I. N. Oliveira
- Departamento de Biofísica e Farmacologia
- Universidade Federal do Rio Grande do Norte
- Natal
- Brazil
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