Insight into the structural requirements of thiophene-3-carbonitriles-based MurF inhibitors by 3D-QSAR, molecular docking and molecular dynamics study

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.

Keywords:

• Thiophene-3-carbonitriles
• MurF inhibitors
• three-dimensional quantitative structure-activity relationship
• docking
• molecular dynamics

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was supported by the Science and Engineering Research Board, Government of India [No. EMR/2016/002981].