Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting molecules

Abstract

Here we report on the structure-based optimization of antibody-recruiting molecules targeting HIV gp120 (ARM-H). These studies have leveraged a combination of medicinal chemistry, biochemical and cellular assay analysis, and computation. Our findings have afforded an optimized analog of ARM-H, which is ~1000 fold more potent in gp120-binding and MT-2 antiviral assays than our previously reported derivative. Furthermore, computational analysis, taken together with experimental data, provides evidence that azaindole- and indole-based attachment inhibitors bind gp120 at an accessory hydrophobic pocket beneath the CD4-binding site and can also adopt multiple unique binding modes in interacting with gp120. These results are likely to prove highly enabling in the development of novel HIV attachment inhibitors, and more broadly, they suggest novel applications for ARMs as probes of conformationally flexible systems.

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

“…In 4TVP compound 1 is inserted into a small cavity decorated by P206, K207, V208, S209, F210, R304, G379, I439, and Q440, stabilized only by hydrophobic and van der Waals contacts. Interestingly, of the residues in this backside binding site, F210 forms a small hydrophobic accessory pocket in the CD4 bound conformation of gp120 where the BMS compounds should likely access when the gate-keeper residues W112 and F382 are open; 36 R304 is part of the V3 loop and I439 and Q440 are part of the V5 loop. It is worth noting that for 2, which differs from the parent compound 1 only in (i) the addition of a fluorine ortho to the chlorine on the region I phenyl and (ii) an N -methyl group at region III, no docking poses on the 4TVP back-side were generated.…”

Peptide Triazole Inactivators of HIV-1 Utilize a Conserved Two-Cavity Binding Site at the Junction of the Inner and Outer Domains of Env gp120

“…38 This priming action of BMS compounds was attributed mainly to interaction with the inner domain layer 2 α 1 helix. 38 Parker et al 40 reported a putative site on gp120 for BMS compounds, that is composed of a hydrophobic cavity in the inner domain gated by Trp112 and Phe382 and that could be accessible during the spontaneous conformational sampling of the Env trimer. 40 Interestingly, Langley et al 31 recently published a hypothetical mode of action for the BMS inhibitors by targeting a hydrophobic cleft in the unliganded Env gp120 where CD4 binding site is not formed (misfolded bridging sheet).…”

“…38 Parker et al 40 reported a putative site on gp120 for BMS compounds, that is composed of a hydrophobic cavity in the inner domain gated by Trp112 and Phe382 and that could be accessible during the spontaneous conformational sampling of the Env trimer. 40 Interestingly, Langley et al 31 recently published a hypothetical mode of action for the BMS inhibitors by targeting a hydrophobic cleft in the unliganded Env gp120 where CD4 binding site is not formed (misfolded bridging sheet). 31 In the current work, we also found that this exposed hydrophobic region appears to be targeted by the PT components.…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…In 2014, the same lab reported the structure‐guided optimization of ARMs targeting HIV gp120, which generated the advanced analogue 192 (derived from 193 ). This is ~1000‐fold more active in gp120‐binding and MT‐2‐based antiviral assays than 190 (Figure ) …”

“…This is~1000-fold more active in gp120-binding and MT-2-based antiviral assays than 190 ( Figure 28). 171 Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed at high levels in many forms of prostate cancer and is thought to be an important target for the drug design of prostate carcinoma. A series of ARMs that enhance antibody-mediated immune recognition of prostate cancer cells was recently disclosed.…”