TY - DATA T1 - Insight into the structural requirements of thiophene-3-carbonitriles-based MurF inhibitors by 3D-QSAR, molecular docking and molecular dynamics study PY - 2017/08/03 AU - Mohammed Afzal Azam AU - Srikanth Jupudi UR - https://tandf.figshare.com/articles/journal_contribution/Insight_into_the_structural_requirements_of_thiophene-3-carbonitriles-based_MurF_inhibitors_by_3D-QSAR_molecular_docking_and_molecular_dynamics_study/5271583 DO - 10.6084/m9.figshare.5271583.v1 L4 - https://ndownloader.figshare.com/files/9019687 KW - Thiophene-3-carbonitriles KW - MurF inhibitors KW - three-dimensional quantitative structure-activity relationship KW - docking KW - molecular dynamics 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. ER -