In Silico based Virtual Screening and Mixed Mode QM/MM Calculation Identifies Caffeine Scaffold for Designing Potential Inhibitors for Tyrosyl tRNA Synthetase of Mycobacterium tuberculosis

摘要

Aminoacyl tRNA synthetases are novel antibacterial drug target because of their important role in protein synthesis. In this study, we performed high throughput virtual screening of 205883 compounds from Asinex ligand database to identify potential specific inhibitors for Tyrosyl tRNA synthetase of Mycobacterium tuberculosis (MtbTyrRS). Compounds are ranked based on the glide extra precision docking score. It is noted that the top ranked compounds have caffeine scaffold. The top five caffeine analogs are further evaluated for other drug-like properties. The binding energies of caffeine analogs are estimated using mixed mode quantum mechanics/molecular mechanics calculation. The results show that these caffeine analogs have good absorption, distribution, metabolism, and excretion properties and high binding affinity to the MtbTyrRS. This suggests that caffeine could be a new scaffold for designing inhibitors against Tyrosyl tRNA synthetase of M. tuberculosis. The top five caffeine analogs are also subjected to docking calculations with human cytosolic and mitochondrial Tyrosyl tRNA synthetases to ascertain their specificities toward MtbTyrRS. The comparative docking studies indicate that the top five caffeine analogs are specific for MtbTyrRS. (c) 2014 Wiley Periodicals, Inc.