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

Journal of Chemical Sciences

CHINMAYEE CHOUDHURY1¹  U DEVA PRIYAKUMAR1¹  G NARAHARI SASTRY1¹ 

[1] Centre for Molecular Modelling, Indian Institute of Chemical Technology, Hyderabad, India$$

关键词: Virtual screening;    pharmacophore model;    docking;    tuberculosis;    HIV;    ADMET filters;    drug repositioning;    poly-pharmacology.;   

DOI  :  

来源: Indian Academy of Sciences

【 摘 要 】

Multidrug resistance in Mycobacterium tuberculosis (M. Tb) and its coexistence with HIV arethe 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 importantM. Tb target considering the above challenges. Five ligand-based pharmacophore models were generatedfrom 40 different conformations of the cofactors of CmaA1 taken from molecular dynamics (MD) simulationstrajectories of CmaA1. The screening abilities of these models were validated by screening 23 inhibitors and1398 non-inhibitors of CmaA1. A VS protocol was designed with four levels of screening i.e., ligand-basedpharmacophore screening, structure-based pharmacophore screening, docking and absorption, distribution,metabolism, excretion and the toxicity (ADMET) filters. In an attempt towards repurposing the existing drugsto inhibit CmaA1, 6,429 drugs reported in DrugBank were considered for screening. To find compounds thatinhibit multiple targets of M. Tb as well as HIV, we also chose 701 and 11,109 compounds showing activitybelow 1 μM range on M. Tb and HIV cell lines, respectively, collected from ChEMBL database. Thus, a totalof 18,239 compounds were screened against CmaA1, and 12 compounds were identified as potential hits forCmaA1 at the end of the fourth step. Detailed analysis of the structures revealed these compounds to interactwith key active site residues of CmaA1.

【 授权许可】

Unknown