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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Microbiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2022.818714/full |
| _version_ | 1818205805916192768 |
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| author | Niranjan Kumar Rakesh Srivastava Raj Kumar Mongre Raj Kumar Mongre Chandra Bhushan Mishra Amit Kumar Amit Kumar Rosy Khatoon Atanu Banerjee Md Ashraf-Uz-Zaman Harpreet Singh Andrew M. Lynn Myeong-Sok Lee Amresh Prakash |
| author_facet | Niranjan Kumar Rakesh Srivastava Raj Kumar Mongre Raj Kumar Mongre Chandra Bhushan Mishra Amit Kumar Amit Kumar Rosy Khatoon Atanu Banerjee Md Ashraf-Uz-Zaman Harpreet Singh Andrew M. Lynn Myeong-Sok Lee Amresh Prakash |
| author_sort | Niranjan Kumar |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-12T04:02:59Z |
| format | Article |
| id | doaj.art-60ba41a1cebf4db481344a1686ad980b |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-12T04:02:59Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-60ba41a1cebf4db481344a1686ad980b2022-12-22T00:38:52ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2022-05-011310.3389/fmicb.2022.818714818714Identifying the Novel Inhibitors Against the Mycolic Acid Biosynthesis Pathway Target “mtFabH” of Mycobacterium tuberculosisNiranjan Kumar0Rakesh Srivastava1Raj Kumar Mongre2Raj Kumar Mongre3Chandra Bhushan Mishra4Amit Kumar5Amit Kumar6Rosy Khatoon7Atanu Banerjee8Md Ashraf-Uz-Zaman9Harpreet Singh10Andrew M. Lynn11Myeong-Sok Lee12Amresh Prakash13School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, IndiaSchool of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, IndiaMolecular Cancer Biology Laboratory, Cellular Heterogeneity Research Center, Department of Biosystem, Sookmyung Women’s University, Seoul, South KoreaDepartment of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, United StatesIndian Council of Medical Research–Computational Genomics Centre, All India Institute of Medical Research, New Delhi, IndiaAmity Institute of Integrative Sciences and Health, Amity University, Gurugram, IndiaAmity Institute of Biotechnology, Amity University, Gurugram, IndiaAmity Institute of Biotechnology, Amity University, Gurugram, IndiaDepartment of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, United StatesIndian Council of Medical Research–Computational Genomics Centre, All India Institute of Medical Research, New Delhi, IndiaSchool of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, IndiaMolecular Cancer Biology Laboratory, Cellular Heterogeneity Research Center, Department of Biosystem, Sookmyung Women’s University, Seoul, South KoreaAmity Institute of Integrative Sciences and Health, Amity University, Gurugram, IndiaMycolic 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.https://www.frontiersin.org/articles/10.3389/fmicb.2022.818714/fullMycobacterium tuberculosismycolic acidsmtFabHinhibitorMD simulationMM/PBSA |
| spellingShingle | Niranjan Kumar Rakesh Srivastava Raj Kumar Mongre Raj Kumar Mongre Chandra Bhushan Mishra Amit Kumar Amit Kumar Rosy Khatoon Atanu Banerjee Md Ashraf-Uz-Zaman Harpreet Singh Andrew M. Lynn Myeong-Sok Lee Amresh Prakash Identifying the Novel Inhibitors Against the Mycolic Acid Biosynthesis Pathway Target “mtFabH” of Mycobacterium tuberculosis Frontiers in Microbiology Mycobacterium tuberculosis mycolic acids mtFabH inhibitor MD simulation MM/PBSA |
| 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 | Mycobacterium tuberculosis mycolic acids mtFabH inhibitor MD simulation MM/PBSA |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2022.818714/full |
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