In Silico-Guided Discovery of Potential HIV-1 Entry Inhibitors Mimicking bNAb N6: Virtual Screening, Docking, Molecular Dynamics, and Post-Molecular Modeling Analysis

Abstract

An integrated computational approach to in silico drug design was used to identify novel HIV-1 entry inhibitor scaffolds mimicking broadly neutralizing antibody (bNAb) N6 targeting CD4-binding site of the viral gp120 protein. This computer-based approach included (i) generation of pharmacophore models representing 3D-arrangements of chemical functionalities that make bNAb N6 active towards CD4-binding site of gp120, (ii) shape and pharmacophore-based identification of the N6-mimetic candidates by a web-oriented virtual screening platform Pharmit, (iii) molecular docking of the identified compounds with gp120, (iv) optimization of the docked ligand/gp120 complexes using semiempirical quantum chemical method PM7, and (v) molecular dynamics simulations of the docked structures followed by binding free energy calculations. As a result, six hits able to mimic the key interactions of N6 with the Phe-43 cavity of gp120 were selected as the most probable N6-mimetic candidates. The pivotal role in the interaction of these compounds with gp120 is shown to play multiple van der Waals contacts with conserved residues of the hydrophobic Phe-43 cavity critical for the HIV-1 binding to cellular receptor CD4, as well as hydrogen bond with Asp-368_gp120 that increase the chemical affinity without activating unwanted allosteric effect. According to the data of molecular dynamics, the complexes of the identified molecules with gp120 are energetically stable and show the lower values of binding free energy compared with the HIV-1 entry inhibitors NBD-11021 and DMJ-II-121 used in the calculations as a positive control. Taken together, the findings obtained suggest that these compounds may serve as promising scaffolds for the development of novel, highly potent and broad anti-HIV-1 therapeutics.