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Identifying the Novel Inhibitors Against the Mycolic Acid Biosynthesis Pathway Target “mtFabH” of Mycobacterium tuberculosis
Mycolic acids are the key constituents of mycobacterial cell wall, which protect the bacteria from antibiotic susceptibility, helping to subvert and escape from the host immune system. Thus, the enzymes involved in regulating and biosynthesis of mycolic acids can be explored as potential drug target...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9121832/ https://www.ncbi.nlm.nih.gov/pubmed/35602011 http://dx.doi.org/10.3389/fmicb.2022.818714 |
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author | Kumar, Niranjan Srivastava, Rakesh Mongre, Raj Kumar Mishra, Chandra Bhushan Kumar, Amit Khatoon, Rosy Banerjee, Atanu Ashraf-Uz-Zaman, Md Singh, Harpreet Lynn, Andrew M. Lee, Myeong-Sok Prakash, Amresh |
author_facet | Kumar, Niranjan Srivastava, Rakesh Mongre, Raj Kumar Mishra, Chandra Bhushan Kumar, Amit Khatoon, Rosy Banerjee, Atanu Ashraf-Uz-Zaman, Md Singh, Harpreet Lynn, Andrew M. Lee, Myeong-Sok Prakash, Amresh |
author_sort | Kumar, Niranjan |
collection | PubMed |
description | Mycolic acids are the key constituents of mycobacterial cell wall, which protect the bacteria from antibiotic susceptibility, helping to subvert and escape from the host immune system. Thus, the enzymes involved in regulating and biosynthesis of mycolic acids can be explored as potential drug targets to kill Mycobacterium tuberculosis (Mtb). Herein, Kyoto Encyclopedia of Genes and Genomes is used to understand the fatty acid metabolism signaling pathway and integrative computational approach to identify the novel lead molecules against the mtFabH (β-ketoacyl-acyl carrier protein synthase III), the key regulatory enzyme of the mycolic acid pathway. The structure-based virtual screening of antimycobacterial compounds from ChEMBL library against mtFabH results in the selection of 10 lead molecules. Molecular binding and drug-likeness properties of lead molecules compared with mtFabH inhibitor suggest that only two compounds, ChEMBL414848 (C1) and ChEMBL363794 (C2), may be explored as potential lead molecules. However, the spatial stability and binding free energy estimation of thiolactomycin (TLM) and compounds C1 and C2 with mtFabH using molecular dynamics simulation, followed by molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) indicate the better activity of C2 (ΔG = −14.18 kcal/mol) as compared with TLM (ΔG = −9.21 kcal/mol) and C1 (ΔG = −13.50 kcal/mol). Thus, compound C1 may be explored as promising drug candidate for the structure-based drug designing of mtFabH inhibitors in the therapy of Mtb. |
format | Online Article Text |
id | pubmed-9121832 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-91218322022-05-21 Identifying the Novel Inhibitors Against the Mycolic Acid Biosynthesis Pathway Target “mtFabH” of Mycobacterium tuberculosis Kumar, Niranjan Srivastava, Rakesh Mongre, Raj Kumar Mishra, Chandra Bhushan Kumar, Amit Khatoon, Rosy Banerjee, Atanu Ashraf-Uz-Zaman, Md Singh, Harpreet Lynn, Andrew M. Lee, Myeong-Sok Prakash, Amresh Front Microbiol Microbiology Mycolic acids are the key constituents of mycobacterial cell wall, which protect the bacteria from antibiotic susceptibility, helping to subvert and escape from the host immune system. Thus, the enzymes involved in regulating and biosynthesis of mycolic acids can be explored as potential drug targets to kill Mycobacterium tuberculosis (Mtb). Herein, Kyoto Encyclopedia of Genes and Genomes is used to understand the fatty acid metabolism signaling pathway and integrative computational approach to identify the novel lead molecules against the mtFabH (β-ketoacyl-acyl carrier protein synthase III), the key regulatory enzyme of the mycolic acid pathway. The structure-based virtual screening of antimycobacterial compounds from ChEMBL library against mtFabH results in the selection of 10 lead molecules. Molecular binding and drug-likeness properties of lead molecules compared with mtFabH inhibitor suggest that only two compounds, ChEMBL414848 (C1) and ChEMBL363794 (C2), may be explored as potential lead molecules. However, the spatial stability and binding free energy estimation of thiolactomycin (TLM) and compounds C1 and C2 with mtFabH using molecular dynamics simulation, followed by molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) indicate the better activity of C2 (ΔG = −14.18 kcal/mol) as compared with TLM (ΔG = −9.21 kcal/mol) and C1 (ΔG = −13.50 kcal/mol). Thus, compound C1 may be explored as promising drug candidate for the structure-based drug designing of mtFabH inhibitors in the therapy of Mtb. Frontiers Media S.A. 2022-05-06 /pmc/articles/PMC9121832/ /pubmed/35602011 http://dx.doi.org/10.3389/fmicb.2022.818714 Text en Copyright © 2022 Kumar, Srivastava, Mongre, Mishra, Kumar, Khatoon, Banerjee, Ashraf-Uz-Zaman, Singh, Lynn, Lee and Prakash. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Kumar, Niranjan Srivastava, Rakesh Mongre, Raj Kumar Mishra, Chandra Bhushan Kumar, Amit Khatoon, Rosy Banerjee, Atanu Ashraf-Uz-Zaman, Md Singh, Harpreet Lynn, Andrew M. Lee, Myeong-Sok Prakash, Amresh Identifying the Novel Inhibitors Against the Mycolic Acid Biosynthesis Pathway Target “mtFabH” of Mycobacterium tuberculosis |
title | Identifying the Novel Inhibitors Against the Mycolic Acid Biosynthesis Pathway Target “mtFabH” of Mycobacterium tuberculosis |
title_full | Identifying the Novel Inhibitors Against the Mycolic Acid Biosynthesis Pathway Target “mtFabH” of Mycobacterium tuberculosis |
title_fullStr | Identifying the Novel Inhibitors Against the Mycolic Acid Biosynthesis Pathway Target “mtFabH” of Mycobacterium tuberculosis |
title_full_unstemmed | Identifying the Novel Inhibitors Against the Mycolic Acid Biosynthesis Pathway Target “mtFabH” of Mycobacterium tuberculosis |
title_short | Identifying the Novel Inhibitors Against the Mycolic Acid Biosynthesis Pathway Target “mtFabH” of Mycobacterium tuberculosis |
title_sort | identifying the novel inhibitors against the mycolic acid biosynthesis pathway target “mtfabh” of mycobacterium tuberculosis |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9121832/ https://www.ncbi.nlm.nih.gov/pubmed/35602011 http://dx.doi.org/10.3389/fmicb.2022.818714 |
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