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Journal of Chemical Sciences

, Volume 128, Issue 5, pp 719–732 | Cite as

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

  • CHINMAYEE CHOUDHURY
  • U DEVA PRIYAKUMAREmail author
  • G NARAHARI SASTRY
Article

Abstract

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 μM 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.

Graphical Abstract

The paper presents generation of dynamic ligand-based pharmacophore model for Mycobacterial cyclopropane synthase and their validation. Aiming towards drug repositioning and selection of multi-target inhibitors, selected compounds from DrugBank and ChEMBL have been screened by a four-step virtual screening using the models and 12 potential compounds are identified.

Keywords

Virtual screening pharmacophore model docking tuberculosis HIV ADMET filters drug repositioning poly-pharmacology 

Notes

Acknowledgements

CC thanks Department of Science and Technology (DST), New Delhi for financial assistance through INSPIRE fellowship. UDP thanks DAE-BRNS for financial assistance. GNS thanks CSIR, New Delhi for financial support in the form of XII five year project (GENESIS).

Supplementary material

12039_2016_1069_MOESM1_ESM.pdf (702 kb)
(PDF 702 KB)

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Copyright information

© Indian Academy of Sciences 2016

Authors and Affiliations

  • CHINMAYEE CHOUDHURY
    • 1
    • 2
  • U DEVA PRIYAKUMAR
    • 2
    Email author
  • G NARAHARI SASTRY
    • 1
  1. 1.Centre for Molecular ModellingIndian Institute of Chemical TechnologyHyderabadIndia
  2. 2.Centre for Computational Natural Sciences and BioinformaticsInternational Institute of Information and TechnologyHyderabadIndia

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