Dynamic ligand-based pharmacophore modeling and virtual screening to identify mycobacterial cyclopropane synthase inhibitors

Multidrug resistance in Mycobacterium tuberculosis (M. Tb) and its coexistence with HIV are the biggest therapeutic challenges in anti-M. Tb drug discovery. The current study reports a Virtual Screening (VS) strategy to identify potential inhibitors of Mycobacterial cyclopropane synthase (CmaA1), an important M. Tb target considering the above challenges. Five ligand-based pharmacophore models were generated from 40 different conformations of the cofactors of CmaA1 taken from molecular dynamics (MD) simulations trajectories of CmaA1. The screening abilities of these models were validated by screening 23 inhibitors and 1398 non-inhibitors of CmaA1. A VS protocol was designed with four levels of screening i.e., ligand-based pharmacophore screening, structure-based pharmacophore screening, docking and absorption, distribution, metabolism, excretion and the toxicity (ADMET) filters. In an attempt towards repurposing the existing drugs to inhibit CmaA1, 6,429 drugs reported in DrugBank were considered for screening. To find compounds that inhibit multiple targets of M. Tb as well as HIV, we also chose 701 and 11,109 compounds showing activity below 1 mu M range on M. Tb and HIV cell lines, respectively, collected from ChEMBL database. Thus, a total of 18,239 compounds were screened against CmaA1, and 12 compounds were identified as potential hits for CmaA1 at the end of the fourth step. Detailed analysis of the structures revealed these compounds to interact with key active site residues of CmaA1.