Abstract

A 3D-QSAR selectivity analysis of 53 adamantyl heteroaryl urea derivatives active against M. tuberculosis is reported. These analogs inhibit Mycobacterial Membrane Protein Large 3 (MmpL3), a proposed transporter for cell wall mycolic acids. However, these analogs also exhibit affinity towards human soluble epoxide hydrolase (sEH) enzyme, making them pharmacologically undesirable. Thus, COMFA and CoMSIA selective studies viz ligand and receptor-based alignment has been described to evaluate key pharmacophoric structural features that may possibly play a crucial role for selective inhibition. This hypothesis was experimentally validated and successfully tested on four novel adamantyl urea based derivatives with known biological activity. Therefore, this approach may pave way to novel specific inhibitors in tuberculosis drug discovery process.

Keywords: CoMFA, CoMSIA, docking, homology modelling, human sEH, MmpL3, tuberculosis.