Molecular Dynamics Study on Selected Bioactive Phytochemicals as Potential Inhibitors of HIV-1 Subtype C Protease

Francis Oluwole Shode; John Omo-Osagie Uhomoibhi; Kehinde Ademola Idowu; Saheed Sabiu; Krishna Kuben Govender

doi:10.3390/metabo12111155

Molecular Dynamics Study on Selected Bioactive Phytochemicals as Potential Inhibitors of HIV-1 Subtype C Protease

Metabolites. 2022 Nov 21;12(11):1155. doi: 10.3390/metabo12111155.

Authors

Francis Oluwole Shode¹, John Omo-Osagie Uhomoibhi¹, Kehinde Ademola Idowu¹, Saheed Sabiu¹, Krishna Kuben Govender^{2

3}

Affiliations

¹ Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology (DUT), P.O. Box 1334, Durban 4000, South Africa.
² Department of Chemical Sciences, University of Johannesburg, Doornfontein Campus, P.O. Box 17011, Johannesburg 2028, South Africa.
³ National Institute for Theoretical and Computational Sciences, NITHeCS, Stellenbosch 7602, South Africa.

Abstract

Acquired immunodeficiency syndrome (AIDS), one of the deadliest global diseases, is caused by the Human Immunodeficiency Virus (HIV). To date, there are no known conventional drugs that can cure HIV/AIDS, and this has prompted continuous scientific efforts in the search for novel and potent anti-HIV therapies. In this study, molecular dynamics simulation (MDS) and computational techniques were employed to investigate the inhibitory potential of bioactive compounds from selected South African indigenous plants against HIV-1 subtype C protease (HIVpro). Of the eight compounds (CMG, MA, UA, CA, BA, UAA, OAA and OA) evaluated, only six (CMG (-9.9 kcal/mol), MA (-9.3 kcal/mol), CA (-9.0 kcal/mol), BA (-8.3 kcal/mol), UAA (-8.5 kcal/mol), and OA (-8.6 kcal/mol)) showed favourable activities against HIVpro and binding landscapes like the reference FDA-approved drugs, Lopinavir (LPV) and Darunavir (DRV), with CMG and MA having the highest binding affinities. Using the structural analysis (root-mean-square deviation (RMSD), fluctuation (RMSF), and radius of gyration (RoG) of the bound complexes with HIVpro after 350 ns, structural evidence was observed, indicating that the six compounds are potential lead candidates for inhibiting HIVpro. This finding was further corroborated by the structural analysis of the enzyme-ligand complexe systems, where structural mechanisms of stability, flexibility, and compactness of the study metabolites were established following binding with HIVpro. Furthermore, the ligand interaction plots revealed that the metabolites interacted hydrophobically with the active site amino residues, with identification of other key residues implicated in HIVpro inhibition for drug design. Overall, this is the first computational report on the anti-HIV-1 activities of CMG and MA, with efforts on their in vitro and in vivo evaluations underway. Judging by the binding affinity, the degree of stability, and compactness of the lead metabolites (CMG, MA, CA, BA, OA, and UAA), they could be concomitantly explored with conventional HIVpro inhibitors in enhancing their therapeutic activities against the HIV-1 serotype.

Keywords: HIV-1 subtype C protease; acquired immunodeficiency syndrome; anti-HIV therapies; human immunodeficiency virus; molecular dynamics simulation (MDS).

Grants and funding

This research received no external funding.