Potential HIV-1 fusion inhibitors mimicking gp41-specific broadly neutralizing antibody 10E8: In silico discovery and prediction of antiviral potency.

An integrated computational approach to in silico drug design was used to identify novel HIV-1 fusion inhibitor scaffolds mimicking broadly neutralizing antibody (bNab) 10E8 targeting the membrane proximal external region (MPER) of the HIV-1 gp41 protein. This computer-based approach included (i) generation of pharmacophore models representing 3D-arrangements of chemical functionalities that make bNAb 10E8 active towards the gp41 MPER segment, (ii) shape and pharmacophore-based identification of the 10E8-mimetic candidates by a web-oriented virtual screening platform pepMMsMIMIC, (iii) high-throughput docking of the identified compounds with the gp41 MPER peptide, and (iv) molecular dynamics simulations of the docked structures followed by binding free energy calculations. As a result, eight hits-able to mimic pharmacophore properties of bNAb 10E8 by specific and effective interactions with the MPER region of the HIV-1 protein gp41 were selected as the most probable 10E8-mimetic candidates.

Computational identification of novel entry inhibitor scaffolds mimicking primary receptor CD4 of HIV-1 gp120.

Virtual screening of novel entry inhibitor scaffolds mimicking primary receptor CD4 of HIV-1 gp120 was carried out in conjunction with evaluation of their potential inhibitory activity by molecular modeling. To do this, pharmacophore models presenting different sets of the hotspots of cellular receptor CD4 for its interaction with gp120 were generated. These models were used as the templates for identification of CD4-mimetic candidates by the pepMMsMIMIC screening platform.

Computational discovery of novel HIV-1 entry inhibitors based on potent and broad neutralizing antibody VRC01.

Computational prediction of novel HIV-1 entry inhibitors presenting peptidomimetics of broadly neutralizing antibody (bNAb) VRC01 was carried out based on the analysis of the X-ray complex of this antibody antigen-binding fragment with the HIV envelope gp120 core. Using these empirical data, peptidomimetic candidates of bNAb VRC01 were identified by a public web-oriented virtual screening platform (pepMMsMIMIC) and models of these candidates bound to gp120 were generated by molecular docking. At the final point, the stability of the complexes of these molecules with gp120 was estimated by molecular dynamics and binding free energy calculations.

In silico design of novel broad anti-HIV-1 agents based on glycosphingolipid β-galactosylceramide, a high-affinity receptor for the envelope gp120 V3 loop.

Novel anti-Human immunodeficiency virus (HIV)-1 agents targeting the V3 loop of envelope protein gp120 were designed by computer modeling based on glycosphingolipid β-galactosylceramide (β-GalCer), which is an alternative receptor allowing HIV-1 entry into CD4-negative cells of neural and colonic origin. Models of these β-GalCer analogs bound to the V3 loops from five various HIV-1 variants were generated by molecular docking and their stability was estimated by molecular dynamics (MDs) and binding free energy simulations. Specific binding to the V3 loop was accomplished primarily by non-conventional XH…π interactions between CH/OH sugar groups of the glycolipids and the conserved V3 residues with π-conjugated side chains.

Discovery of novel anti-HIV-1 agents based on a broadly neutralizing antibody against the envelope gp120 V3 loop: a computational study.

A computer-aided search for novel anti-HIV-1 agents able to mimic the pharmacophore properties of broadly neutralizing antibody (bNAb) 3074 was carried out based on the analysis of X-ray complexes of this antibody Fab with the MN, UR29, and VI191 peptides from the V3 loop of the HIV envelope protein gp120. Using these empirical data, peptidomimetic candidates of bNAb 3074 were identified by a public, web-oriented virtual screening platform (pepMMsMIMIC) and models of these candidates bound to the above V3 peptides were generated by molecular docking. The docking calculations identified four molecules exhibiting a high affinity to all of the V3 peptides.