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High Throughput Virtual Screening and Molecular Dynamics Simulation for Identifying a Putative Inhibitor of Bacterial CTX-M-15
Background: Multidrug resistant bacteria are a major therapeutic challenge. CTX-M-type enzymes are an important group of class A extended-spectrum β-lactamases (ESBLs). ESBLs are the enzymes that arm bacterial pathogens with drug resistance to an array of antibiotics, notably the advanced-generation...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143117/ https://www.ncbi.nlm.nih.gov/pubmed/33919115 http://dx.doi.org/10.3390/antibiotics10050474 |
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author | Shakil, Shazi Rizvi, Syed M. Danish Greig, Nigel H. |
author_facet | Shakil, Shazi Rizvi, Syed M. Danish Greig, Nigel H. |
author_sort | Shakil, Shazi |
collection | PubMed |
description | Background: Multidrug resistant bacteria are a major therapeutic challenge. CTX-M-type enzymes are an important group of class A extended-spectrum β-lactamases (ESBLs). ESBLs are the enzymes that arm bacterial pathogens with drug resistance to an array of antibiotics, notably the advanced-generation cephalosporins. The current need for an effective CTX-M-inhibitor is high. Objective: The aim of the current study was to identify a promising anti-CTX-M-15 ligand whose chemical skeleton could be used as a ‘seed-molecule’ for future drug design against resistant bacteria. Methods: Virtual screening of 5,000,000 test molecules was performed by ‘MCULE Drug Discovery Platform’. ‘ADME analyses’ was performed by ‘SWISS ADME’. TOXICITY CHECKER of MCULE was employed to predict the safety profile of the test molecules. The complex of the ‘Top inhibitor’ with the ‘bacterial CTX-M-15 enzyme’ was subjected to 102.25 ns molecular dynamics simulation. This simulation was run for 3 days on a HP ZR30w workstation. Trajectory analyses were performed by employing the macro ‘md_analyze.mcr’ of YASARA STRUCTURE version 20.12.24.W.64 using AMBER14 force field. YANACONDA macro language was used for complex tasks. Figures, including RMSD and RMSF plots, were generated. Snapshots were acquired after every 250 ps. Finally, two short videos of ‘41 s’ and ‘1 min and 22 s’ duration were recorded. Results: 5-Amino-1-(2H-[1,2,4]triazino[5,6-b]indol-3-yl)-1H-pyrazole-4-carbonitrile, denoted by the MCULE-1352214421-0-56, displayed the most efficient binding with bacterial CTX-M-15 enzyme. This screened molecule significantly interacted with CTX-M-15 via 13 amino acid residues. Notably, nine amino acid residues were found common to avibactam binding (the reference ligand). Trajectory analysis yielded 410 snapshots. The RMSD plot revealed that around 26 ns, equilibrium was achieved and, thereafter, the complex remained reasonably stable. After a duration of 26 ns and onwards until 102.25 ns, the backbone RMSD fluctuations were found to be confined within a range of 0.8–1.4 Å. Conclusion: 5-Amino-1-(2H-[1,2,4]triazino[5,6-b]indol-3-yl)-1H-pyrazole-4-carbonitrile could emerge as a promising seed molecule for CTX-M-15-inhibitor design. It satisfied ADMET features and displayed encouraging ‘simulation results’. Advanced plots obtained by trajectory analyses predicted the stability of the proposed protein-ligand complex. ‘Hands on’ wet laboratory validation is warranted. |
format | Online Article Text |
id | pubmed-8143117 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81431172021-05-25 High Throughput Virtual Screening and Molecular Dynamics Simulation for Identifying a Putative Inhibitor of Bacterial CTX-M-15 Shakil, Shazi Rizvi, Syed M. Danish Greig, Nigel H. Antibiotics (Basel) Article Background: Multidrug resistant bacteria are a major therapeutic challenge. CTX-M-type enzymes are an important group of class A extended-spectrum β-lactamases (ESBLs). ESBLs are the enzymes that arm bacterial pathogens with drug resistance to an array of antibiotics, notably the advanced-generation cephalosporins. The current need for an effective CTX-M-inhibitor is high. Objective: The aim of the current study was to identify a promising anti-CTX-M-15 ligand whose chemical skeleton could be used as a ‘seed-molecule’ for future drug design against resistant bacteria. Methods: Virtual screening of 5,000,000 test molecules was performed by ‘MCULE Drug Discovery Platform’. ‘ADME analyses’ was performed by ‘SWISS ADME’. TOXICITY CHECKER of MCULE was employed to predict the safety profile of the test molecules. The complex of the ‘Top inhibitor’ with the ‘bacterial CTX-M-15 enzyme’ was subjected to 102.25 ns molecular dynamics simulation. This simulation was run for 3 days on a HP ZR30w workstation. Trajectory analyses were performed by employing the macro ‘md_analyze.mcr’ of YASARA STRUCTURE version 20.12.24.W.64 using AMBER14 force field. YANACONDA macro language was used for complex tasks. Figures, including RMSD and RMSF plots, were generated. Snapshots were acquired after every 250 ps. Finally, two short videos of ‘41 s’ and ‘1 min and 22 s’ duration were recorded. Results: 5-Amino-1-(2H-[1,2,4]triazino[5,6-b]indol-3-yl)-1H-pyrazole-4-carbonitrile, denoted by the MCULE-1352214421-0-56, displayed the most efficient binding with bacterial CTX-M-15 enzyme. This screened molecule significantly interacted with CTX-M-15 via 13 amino acid residues. Notably, nine amino acid residues were found common to avibactam binding (the reference ligand). Trajectory analysis yielded 410 snapshots. The RMSD plot revealed that around 26 ns, equilibrium was achieved and, thereafter, the complex remained reasonably stable. After a duration of 26 ns and onwards until 102.25 ns, the backbone RMSD fluctuations were found to be confined within a range of 0.8–1.4 Å. Conclusion: 5-Amino-1-(2H-[1,2,4]triazino[5,6-b]indol-3-yl)-1H-pyrazole-4-carbonitrile could emerge as a promising seed molecule for CTX-M-15-inhibitor design. It satisfied ADMET features and displayed encouraging ‘simulation results’. Advanced plots obtained by trajectory analyses predicted the stability of the proposed protein-ligand complex. ‘Hands on’ wet laboratory validation is warranted. MDPI 2021-04-21 /pmc/articles/PMC8143117/ /pubmed/33919115 http://dx.doi.org/10.3390/antibiotics10050474 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Shakil, Shazi Rizvi, Syed M. Danish Greig, Nigel H. High Throughput Virtual Screening and Molecular Dynamics Simulation for Identifying a Putative Inhibitor of Bacterial CTX-M-15 |
title | High Throughput Virtual Screening and Molecular Dynamics Simulation for Identifying a Putative Inhibitor of Bacterial CTX-M-15 |
title_full | High Throughput Virtual Screening and Molecular Dynamics Simulation for Identifying a Putative Inhibitor of Bacterial CTX-M-15 |
title_fullStr | High Throughput Virtual Screening and Molecular Dynamics Simulation for Identifying a Putative Inhibitor of Bacterial CTX-M-15 |
title_full_unstemmed | High Throughput Virtual Screening and Molecular Dynamics Simulation for Identifying a Putative Inhibitor of Bacterial CTX-M-15 |
title_short | High Throughput Virtual Screening and Molecular Dynamics Simulation for Identifying a Putative Inhibitor of Bacterial CTX-M-15 |
title_sort | high throughput virtual screening and molecular dynamics simulation for identifying a putative inhibitor of bacterial ctx-m-15 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143117/ https://www.ncbi.nlm.nih.gov/pubmed/33919115 http://dx.doi.org/10.3390/antibiotics10050474 |
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