E-pharmacophore based screening to identify potential HIV-1 gp120 and CD4 interaction blockers for wild and mutant types

ABSTRACT

HIV-1 gp120 provides a multistage viral entry process through the conserved CD4 binding site. Hunting of potential blockers can diminish the interaction of gp120 with the CD4 host receptor leading to the suppression of HIV-1 infection. Structure-based pharmacophore virtual screening followed by binding free energy calculation, molecular dynamics (MD) simulation and density functional theory (DFT) calculation is applied to discriminate the potential blockers from six small molecule databases. Five compounds from six databases exhibited vital interactions with key residues ASP368, GLU370, ASN425, MET426, TRP427 and GLY473 of gp120, involved in the binding with CD4, host receptor. Most importantly, compound NCI-254200 displayed strong communication with key residues of wild type and drug resistance single mutant gp120 (M426L and W427V) even in the dynamic condition, evidenced from MD simulation. This investigation provided a potential compound NCI-254200 which may show inhibitory activity against HIV-1 gp120 variant interactions with CD4 host cell receptors.

KEYWORDS:

• HIV-1 gp120
• entry inhibitor
• drug-resistant mutant
• E-pharmacophore
• virtual screening
• molecular dynamics simulations

Acknowledgements

The authors are pleased to acknowledge the research facility provided by Alagappa University.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2021.1901310

Additional information

Funding

This work was supported by the Rashtriya Uchchatar Shiksha Abhiyan - Phase 2.0 (RUSA 2.0) under [Grant sanctioned vide letter No. F. 24-51/2014 - U, Policy (TNMulti-Gen), Department of Education, Government of India, dated: 09 October 2018]; Department of Biotechnology Ministry of Science and Technology, New Delhi, under Grant/Award [No. BT/PR8138/BID/7/458/2013, dated 23 May 2013]; DST-PURSE 2nd Phase Programme under Grant [Order No. SR/PURSE Phase 2/38 G dated 21.02.2017] and FIST [SR/FST/LSI - 667/2016, MHRD] for the financial support.