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An integrated computational approach of molecular dynamics simulations, receptor binding studies and pharmacophore mapping analysis in search of potent inhibitors against tuberculosis.
J Mol Graph Model. 2018 08; 83:17-32.JM

Abstract

Tuberculosis is an infectious chronic disease caused by obligate pathogen Mycobacterium tuberculosis that affects millions of people worldwide. Although many first and second line drugs are available for its treatment, but their irrational use has adversely lead to the emerging cases of multiple drug resistant and extensively drug-resistant tuberculosis. Therefore, there is an intense need to develop novel potent analogues for its treatment. This has prompted us to develop potent analogues against TB. The Mycobacterium tuberculosis genome provides us with number of validated targets to combat against TB. Study of Mtb genome disclosed six epoxide hydrolases (A to F) which convert harmful epoxide into diols and act as a potential drug target for rational drug design. Our current strategy is to develop such analogues which inhibits epoxide hydrolase enzyme present in Mtb genome. To achieve this, we adopted an integrated computational approach involving QSAR, pharmacophore mapping, molecular docking and molecular dynamics simulation studies. The approach envisaged vital information about the role of molecular descriptors, essential pharmacophoric features and binding energy for compounds to bind into the active site of epoxide hydrolase. Molecular docking analysis revealed that analogues exhibited significant binding to Mtb epoxide hydrolase. Further, three docked complexes 2s, 37s and 15s with high, moderate and low docking scores respectively were selected for molecular dynamics simulation studies. RMSD analysis revealed that all complexes are stable with average RMSD below 2 Å throughout the 10 ns simulations. The B-factor analysis showed that the active site residues of epoxide hydrolase are flexible enough to interact with inhibitor. Moreover, to confirm the binding of these urea derivatives, MM-GBSA binding energy analysis were performed. The calculations showed that 37s has more binding affinity (ΔGtotal = -52.24 kcal/mol) towards epoxide hydrolase compared to 2s (ΔGtotal = -51.70 kcal/mol) and 15s (ΔGtotal = -49.97 kcal/mol). The structural features inferred in our study may provide the future directions to the scientists towards the discovery of new chemical entity exhibiting anti-TB property.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Agarwal S
Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar, MP, India.
Verma E
Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar, MP, India.
Kumar V
Department of Plant and Soil Sciences, University of Pretoria, South Africa.
Lall N
Department of Plant and Soil Sciences, University of Pretoria, South Africa.
Sau S
Use-inspired Biomaterials & integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA.
Iyer AK
Use-inspired Biomaterials & integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA; Molecular Imaging Program, Karmanos Cancer Institute, Detroit, MI, USA.
Kashaw SK
Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar, MP, India. Electronic address: sushilkashaw@gmail.com.

MeSH

Amino Acid SequenceAntitubercular AgentsBacterial ProteinsCatalytic DomainDrug DesignHumansHydrogen BondingMolecular Docking SimulationMolecular Dynamics SimulationMolecular StructureProtein BindingQuantitative Structure-Activity RelationshipWorkflow

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29753941

Citation

Agarwal, Shivangi, et al. "An Integrated Computational Approach of Molecular Dynamics Simulations, Receptor Binding Studies and Pharmacophore Mapping Analysis in Search of Potent Inhibitors Against Tuberculosis." Journal of Molecular Graphics & Modelling, vol. 83, 2018, pp. 17-32.
Agarwal S, Verma E, Kumar V, et al. An integrated computational approach of molecular dynamics simulations, receptor binding studies and pharmacophore mapping analysis in search of potent inhibitors against tuberculosis. J Mol Graph Model. 2018;83:17-32.
Agarwal, S., Verma, E., Kumar, V., Lall, N., Sau, S., Iyer, A. K., & Kashaw, S. K. (2018). An integrated computational approach of molecular dynamics simulations, receptor binding studies and pharmacophore mapping analysis in search of potent inhibitors against tuberculosis. Journal of Molecular Graphics & Modelling, 83, 17-32. https://doi.org/10.1016/j.jmgm.2018.04.019
Agarwal S, et al. An Integrated Computational Approach of Molecular Dynamics Simulations, Receptor Binding Studies and Pharmacophore Mapping Analysis in Search of Potent Inhibitors Against Tuberculosis. J Mol Graph Model. 2018;83:17-32. PubMed PMID: 29753941.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An integrated computational approach of molecular dynamics simulations, receptor binding studies and pharmacophore mapping analysis in search of potent inhibitors against tuberculosis. AU - Agarwal,Shivangi, AU - Verma,Ekta, AU - Kumar,Vivek, AU - Lall,Namrita, AU - Sau,Samaresh, AU - Iyer,Arun K, AU - Kashaw,Sushil K, Y1 - 2018/05/03/ PY - 2017/11/17/received PY - 2018/04/26/revised PY - 2018/04/27/accepted PY - 2018/5/14/pubmed PY - 2019/10/24/medline PY - 2018/5/14/entrez KW - Epoxide hydrolase KW - Molecular docking KW - Molecular dynamics simulation KW - Pharmacophore mapping KW - Tuberculosis SP - 17 EP - 32 JF - Journal of molecular graphics & modelling JO - J Mol Graph Model VL - 83 N2 - Tuberculosis is an infectious chronic disease caused by obligate pathogen Mycobacterium tuberculosis that affects millions of people worldwide. Although many first and second line drugs are available for its treatment, but their irrational use has adversely lead to the emerging cases of multiple drug resistant and extensively drug-resistant tuberculosis. Therefore, there is an intense need to develop novel potent analogues for its treatment. This has prompted us to develop potent analogues against TB. The Mycobacterium tuberculosis genome provides us with number of validated targets to combat against TB. Study of Mtb genome disclosed six epoxide hydrolases (A to F) which convert harmful epoxide into diols and act as a potential drug target for rational drug design. Our current strategy is to develop such analogues which inhibits epoxide hydrolase enzyme present in Mtb genome. To achieve this, we adopted an integrated computational approach involving QSAR, pharmacophore mapping, molecular docking and molecular dynamics simulation studies. The approach envisaged vital information about the role of molecular descriptors, essential pharmacophoric features and binding energy for compounds to bind into the active site of epoxide hydrolase. Molecular docking analysis revealed that analogues exhibited significant binding to Mtb epoxide hydrolase. Further, three docked complexes 2s, 37s and 15s with high, moderate and low docking scores respectively were selected for molecular dynamics simulation studies. RMSD analysis revealed that all complexes are stable with average RMSD below 2 Å throughout the 10 ns simulations. The B-factor analysis showed that the active site residues of epoxide hydrolase are flexible enough to interact with inhibitor. Moreover, to confirm the binding of these urea derivatives, MM-GBSA binding energy analysis were performed. The calculations showed that 37s has more binding affinity (ΔGtotal = -52.24 kcal/mol) towards epoxide hydrolase compared to 2s (ΔGtotal = -51.70 kcal/mol) and 15s (ΔGtotal = -49.97 kcal/mol). The structural features inferred in our study may provide the future directions to the scientists towards the discovery of new chemical entity exhibiting anti-TB property. SN - 1873-4243 UR - https://www.unboundmedicine.com/medline/citation/29753941/An_integrated_computational_approach_of_molecular_dynamics_simulations_receptor_binding_studies_and_pharmacophore_mapping_analysis_in_search_of_potent_inhibitors_against_tuberculosis_ DB - PRIME DP - Unbound Medicine ER -
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