Ugwu-Korie, N.Quaye, O.Wright, E.Languon, S.Agyapong, O.Broni, E.Gupta, Y.Kempaiah, P.Kwofie, S.K.2023-04-212023-04-212023Citation: Ugwu-Korie, N.; Quaye, O.; Wright, E.; Languon, S.; Agyapong, O.; Broni, E.; Gupta, Y.; Kempaiah, P.; Kwofie, S.K. Structure-Based Identification of Natural -Product-Derived Compounds with Potential to Inhibit HIV-1 Entry. Molecules 2023, 28, 474. https://doi.org/10.3390/ molecules28020474https://doi.org/10.3390/molecules28020474http://ugspace.ug.edu.gh:8080/handle/123456789/38887Research ArticleBroadly neutralizing antibodies (bNAbs) are potent in neutralizing a wide range of HIV strains. VRC01 is a CD4-binding-site (CD4-bs) class of bNAbs that binds to the conserved CD4- binding region of HIV-1 envelope (env) protein. Natural products that mimic VRC01 bNAbs by interacting with the conserved CD4-binding regions may serve as a new generation of HIV-1 en try inhibitors by being broadly reactive and potently neutralizing. This study aimed to identify compounds that mimic VRC01 by interacting with the CD4-bs of HIV-1 gp120 and thereby inhibit ing viral entry into target cells. Libraries of purchasable natural products were virtually screened against clade A/E recombinant 93TH057 (PDB: 3NGB) and clade B (PDB ID: 3J70) HIV-1 env protein. Protein–ligand interaction profiling from molecular docking and dynamics simulations showed that the compounds had intermolecular hydrogen and hydrophobic interactions with conserved amino acid residues on the CD4-binding site of recombinant clade A/E and clade B HIV-1 gp120. Four potential lead compounds, NP-005114, NP-008297, NP-007422, and NP-007382, were used for cell-based antiviral infectivity inhibition assay using clade B (HXB2) env pseudotype virus (PV). The four compounds inhibited the entry of HIV HXB2 pseudotype viruses into target cells at 50% inhibitory concentrations (IC50) of 15.2 µM (9.7 µg/mL), 10.1 µM (7.5 µg/mL), 16.2 µM (12.7 µg/mL), and 21.6 µM (12.9 µg/mL), respectively. The interaction of these compounds with critical residues of the CD4-binding site of more than one clade of HIV gp120 and inhibition of HIV-1 entry into the target cell demonstrate the possibility of a new class of HIV entry inhibitors.enHIV-1 entryinhibitionCD4-binding siteVRC01Article