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Insight into the structural requirements of thiophene-3-carbonitriles-based MurF inhibitors by 3D-QSAR, molecular docking and molecular dynamics study.
J Recept Signal Transduct Res. 2017 Oct; 37(5):522-534.JR

Abstract

The discovery of clinically relevant inhibitors against MurF enzyme has proven to be a challenging task. In order to get further insight into the structural features required for the MurF inhibitory activity, we performed pharmacophore and atom-based three-dimensional quantitative structure-activity relationship studies for novel thiophene-3-carbonitriles based MurF inhibitors. The five-feature pharmacophore model was generated using 48 inhibitors having IC50 values ranging from 0.18 to 663 μm. The best-fitted model showed a higher coefficient of determination (R2 = 0.978), cross-validation coefficient (Q2 = 0.8835) and Pearson coefficient (0.9406) at four component partial least-squares factor. The model was validated with external data set and enrichment study. The effectiveness of the docking protocol was validated by docking the co-crystallized ligand into the catalytic pocket of MurF enzyme. Further, binding free energy calculated by the molecular mechanics generalized Born surface area approach showed that van der Waals and non-polar solvation energy terms are the main contributors to ligand binding in the active site of MurF enzyme. A 10-ns molecular dynamic simulation was performed to confirm the stability of the 3ZM6-ligand complex. Four new molecules are also designed as potent MurF inhibitors. These results provide insights regarding the development of novel MurF inhibitors with better binding affinity.

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Authors+Show Affiliations

Azam MA
a Department of Pharmaceutical Chemistry , JSS College of Pharmacy (A Constituent College of Jagadguru Sri Sivarathreeswara University, Mysuru) , Udhagamandalam , India.
Jupudi S
a Department of Pharmaceutical Chemistry , JSS College of Pharmacy (A Constituent College of Jagadguru Sri Sivarathreeswara University, Mysuru) , Udhagamandalam , India.

MeSH

Binding SitesCatalytic DomainEnzyme InhibitorsHumansHydrogen BondingLigandsMolecular Docking SimulationMolecular Dynamics SimulationPeptide SynthasesPneumococcal InfectionsProtein BindingQuantitative Structure-Activity RelationshipStreptococcus pneumoniaeThiophenes

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28768454

Citation

Azam, Mohammed Afzal, and Srikanth Jupudi. "Insight Into the Structural Requirements of Thiophene-3-carbonitriles-based MurF Inhibitors By 3D-QSAR, Molecular Docking and Molecular Dynamics Study." Journal of Receptor and Signal Transduction Research, vol. 37, no. 5, 2017, pp. 522-534.
Azam MA, Jupudi S. Insight into the structural requirements of thiophene-3-carbonitriles-based MurF inhibitors by 3D-QSAR, molecular docking and molecular dynamics study. J Recept Signal Transduct Res. 2017;37(5):522-534.
Azam, M. A., & Jupudi, S. (2017). Insight into the structural requirements of thiophene-3-carbonitriles-based MurF inhibitors by 3D-QSAR, molecular docking and molecular dynamics study. Journal of Receptor and Signal Transduction Research, 37(5), 522-534. https://doi.org/10.1080/10799893.2017.1360354
Azam MA, Jupudi S. Insight Into the Structural Requirements of Thiophene-3-carbonitriles-based MurF Inhibitors By 3D-QSAR, Molecular Docking and Molecular Dynamics Study. J Recept Signal Transduct Res. 2017;37(5):522-534. PubMed PMID: 28768454.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insight into the structural requirements of thiophene-3-carbonitriles-based MurF inhibitors by 3D-QSAR, molecular docking and molecular dynamics study. AU - Azam,Mohammed Afzal, AU - Jupudi,Srikanth, Y1 - 2017/08/03/ PY - 2017/8/5/pubmed PY - 2018/4/28/medline PY - 2017/8/4/entrez KW - MurF inhibitors KW - Thiophene-3-carbonitriles KW - docking KW - molecular dynamics KW - three-dimensional quantitative structure-activity relationship SP - 522 EP - 534 JF - Journal of receptor and signal transduction research JO - J Recept Signal Transduct Res VL - 37 IS - 5 N2 - The discovery of clinically relevant inhibitors against MurF enzyme has proven to be a challenging task. In order to get further insight into the structural features required for the MurF inhibitory activity, we performed pharmacophore and atom-based three-dimensional quantitative structure-activity relationship studies for novel thiophene-3-carbonitriles based MurF inhibitors. The five-feature pharmacophore model was generated using 48 inhibitors having IC50 values ranging from 0.18 to 663 μm. The best-fitted model showed a higher coefficient of determination (R2 = 0.978), cross-validation coefficient (Q2 = 0.8835) and Pearson coefficient (0.9406) at four component partial least-squares factor. The model was validated with external data set and enrichment study. The effectiveness of the docking protocol was validated by docking the co-crystallized ligand into the catalytic pocket of MurF enzyme. Further, binding free energy calculated by the molecular mechanics generalized Born surface area approach showed that van der Waals and non-polar solvation energy terms are the main contributors to ligand binding in the active site of MurF enzyme. A 10-ns molecular dynamic simulation was performed to confirm the stability of the 3ZM6-ligand complex. Four new molecules are also designed as potent MurF inhibitors. These results provide insights regarding the development of novel MurF inhibitors with better binding affinity. SN - 1532-4281 UR - https://www.unboundmedicine.com/medline/citation/28768454/Insight_into_the_structural_requirements_of_thiophene_3_carbonitriles_based_MurF_inhibitors_by_3D_QSAR_molecular_docking_and_molecular_dynamics_study_ L2 - https://www.tandfonline.com/doi/full/10.1080/10799893.2017.1360354 DB - PRIME DP - Unbound Medicine ER -
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