Computational Evaluation of HIV-1 gp120 Conformations of Soluble Trimeric gp140 Structures as Targets for de Novo Docking of First- and Second-Generation Small-Molecule CD4 Mimics

Abstract

Small-molecule CD4 mimics (SMCM’s) bind to the gp120 subunit of the HIV-1 envelope glycoprotein (Env) and have been optimized to block cell infection in vitro. The lack of the V1/2 and V3 loops and the presence of the β2/3 and β20/21 strands (bridging sheet) in the available structures of the monomeric gp120 core may limit its applicability as a target for further synthetic optimization of SMCM potency and/or breadth. Here, we employ a combination of binding-site search, docking, estimation of protein–ligand interaction energy, all-atom molecular dynamics, and ELISA-based CD4-binding competition assays to create, characterize, and rationalize models of first- and second-generation of SMCM’s bound to the distinct, trimeric BG505 SOSIP.664 structures 4NCO and 4TVP containing V1/2 and V3 loops with no bridging sheet. We demonstrate that the in silico neutralization of the highly conserved D368 is necessary to obtain the correct orientation of SMCM in their binding site when docking against the monomeric gp120 core. The computational results correlate with IC50’s measured in CD4 binding competition ELISA and with KD’s measured on gp120 core monomer. This supports the hypothesis that the 4NCO trimeric structure represents a viable target for further SMCM’s optimization with advantages over both the 4TVP trimer and gp120 core monomer. Finally, the docking protocol has been optimized to screen compounds that can clearly interact with the highly conserved residue D368, increasing the likelihood of future optimizations to arrive at SMCM’s with a broader spectrum of activity.

Recognition of HIV-inactivating peptide triazoles by the recombinant soluble Env trimer, BG505 SOSIP.664

“…The SOSIP coordinates (PDB 4NCO 12 ) have been recently used as a productive tool in structure-based design of different gp120 targeting ligands. 23 Based on the gp120-gp41 interface in the recently reported SOSIP trimer structure, 16 along with the hypothesized SOSIP-PT binding model presented here, we surmise that PT interactions with Env trimer gp120 could well perturb the a1-helix and other inner domain elements of gp120 involved in interactions with gp41 of Env protein. 12,14,32,35 In this view, disruption of these layers by PT binding may be an important cause of observed gp120 shedding from the virion triggered by PTs, leading to irreversible virus inactivation.…”

“…The ability to obtain putative binding poses matching the mutational data using the SOSIP coordinates further supports this hypothesis. The SOSIP coordinates (PDB 4NCO 12 ) have been recently used as a productive tool in structure‐based design of different gp120 targeting ligands …”

“…De novo flexible docking (allowing flexible movement of the W112 side‐chain) was performed, based on earlier docking observations, on the gp140 protomer extracted from the crystal structure of BG505 SOSIP.664 (4NCO) . This structure has recently been validated as a target for investigating gp120‐binding ligands . For docking the ferrocene containing peptide with the protein in a high accuracy mode, the maximum number of evaluations in Autodock 4.2 (25,000,000) was used.…”

“…We found that both peptides 1 and 2 competed with receptor CD4IgG2 for binding to SOSIP proteins and could be modeled into a two‐subsite binding cavity, in the trimer protomer, that is similar to that found in gp120 monomer . In the light of advancing SOSIP high resolution structures and their use for computation‐based ligand design, the results reported here provide a framework for optimization of PT virus inactivators as well as for understanding their structural mechanism of inactivation upon binding to HIV envelope protein.…”

Computational study of HIV gp120 as a target for polyanionic entry inhibitors: Exploiting the V3 loop region

“…For example, Li et al [ 94 ] examined the binding of BMS-488043 to gp120 using structures selected at regular intervals from an MD simulation, but their structures had truncated V1/V2 and V3 loops, so binding to the loops could not be considered. More recently, Moraca et al [ 95 ] used crystal structures with PDB ID codes 4NCO [ 96 ] and 4TVP [ 97 ], which include nearly intact V1/V2/V3 loops, as the basis for their studies and focused on identifying small-molecule CD4 mimetics and used a combination of approaches that included molecular docking and MD simulations. Notably, the region at which these mimetics bound was within the gp120-CD4 binding interface and away from the V3 loop that was the focus of our study.…”