3D-QSAR Selectivity Analysis of 1-Adamantyl-3-Heteroaryl Urea Analogs as Potent Inhibitors of Mycobacterium tuberculosis

Publisher： Bentham Science Publishers

E-ISSN： 1875-6697|11|2|164-183

ISSN： 1573-4099

Source： Current Computer - Aided Drug Design, Vol.11, Iss.2, 2015-09, pp. : 164-183

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Abstract

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

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