192 Computer-aided search for novel anti-HIV-1 agents presenting peptidomimetics of broadly neutralizing antibodies against the virus envelope GP120 V3 loop

Abstract

Computer-aided search for novel anti-HIV-1 agents that are able to imitate the pharmacophore properties of the antigen-binding site of a broadly neutralizing mAb 3074 against the envelope gp120 V3 loop was carried out followed by evaluation of their potential inhibitory activity by molecular modeling. In doing so, the following problems were solved: (1) the mAb 3074 amino acid residues responsible for specific binding to the HIV-1 V3 loop were identified from the X-ray structures of this antibody Fab in complexes with the MN, UR29, and VI191 V3 peptides (Jiang et al., 2010); (2) using these data, 2039 possible mAb-3074 peptidomimetics were found by pepMMsMIMIC presenting a public, web-oriented virtual screening platform (Floris et al., 2011); (3) the complexes of these compounds with the above V3 peptides were built by molecular docking and, based on their analysis, the four molecules exhibiting a high affinity to V3 in the in silico studies were selected as the most probable peptidomimetics of mAb 3074 (Figure 1); and (4) stability of the complexes of these molecules with the MN, UR29, and VI191 V3 peptides was estimated by molecular dynamics and free energy simulations. As a result, a key role in specific binding of the selected compounds to the V3 loop was shown to belong to π-π interactions between their aromatic rings and the conserved Phe20 and/or Tyr21 of the V3 immunogenic crown. Similarly to mAb 3074, these compounds were found to block the tip of the V3 loop forming its invariant structural motif, which contains residues critical for cell tropism (Andrianov et al., 2011; Andrianov et al., 2012). In addition, the complexes of interest do not undergo significant changes within the molecular dynamics calculations, exhibiting the low values of free energy of their formation. In this context, the compounds given in Figure 1 are considered as the promising basic structures for the design of novel, potent, and broad anti-HIV-1 drugs.