Discovery of novel inhibitors of Mycobacterium tuberculosis MurG: homology modelling, structure based pharmacophore, molecular docking, and molecular dynamics simulations

Abstract

MurG (Rv2153c) is a key player in the biosynthesis of the peptidoglycan layer in Mycobacterium tuberculosis (Mtb). This work is an attempt to highlight the structural and functional relationship of Mtb MurG, the three-dimensional (3D) structure of protein was constructed by homology modelling using Discovery Studio 3.5 software. The quality and consistency of generated model was assessed by PROCHECK, ProSA and ERRAT. Later, the model was optimized by molecular dynamics (MD) simulations and the optimized model complex with substrate Uridine-diphosphate-N-acetylglucosamine (UD1) facilitated us to employ structure-based virtual screening approach to obtain new hits from Asinex database using energy-optimized pharmacophore modelling (e-pharmacophore). The pharmacophore model was validated using enrichment calculations, and finally, validated model was employed for high-throughput virtual screening and molecular docking to identify novel Mtb MurG inhibitors. This study led to the identification of 10 potential compounds with good fitness, docking score, which make important interactions with the protein active site. The 25 ns MD simulations of three potential lead compounds with protein confirmed that the structure was stable and make several non-bonding interactions with amino acids, such as Leu290, Met310 and Asn167. Hence, we concluded that the identified compounds may act as new leads for the design of Mtb MurG inhibitors.

Keywords:

• MurG
• homology modelling
• e-pharmacophore
• virtual screening
• molecular docking and MD simulations

Acknowledgements

The authors are thankful to the BITS-Pilani Hyderabad Campus for proving the access to Schrödinger software, and Dean, School of Computer and Information Sciences, University of Hyderabad, for computational facilities. S.S. acknowledges the UGC-D.S. Kothari postdoctoral fellowship.