Design and computational support for the binding stability of a new CCR5/CXCR4 dual tropic inhibitor: Computational design of a CCR5/CXCR4 drug.

The human immunodeficiency virus (HIV) infects healthy human cells by binding to the glycoprotein cluster of differentiation 4 receptors on the surface of helper T-cells, along with either of two chemokine receptors, CC chemokine receptor type 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4). Recently, a pyrazolo-piperdine ligand was synthesized and the corresponding biological data showed good binding to both chemokine receptors, effectively blocking HIV-1 entry. Here, we exhaustively assess the atomistic binding interactions of this compound with both CCR5 and CXCR4, and we find that binding is driven by π-stacking interactions between aromatic rings on the ligand and receptor residues, as well as electrostatic interactions involving the protonated piperidine nitrogen. However, these favorable binding interactions were partially offset by unfavorable desolvation of active site glutamates and aspartates, prompting our proposal of a new, synthetically-accessible derivative designed to increase the electrostatic interactions without compromising the π-stacking features.