Applying in silico tools to the discovery of novel CXCR4 inhibitors

Abstract

The process of HIV entry begins with the binding of the viral envelope glycoprotein gp120 to both the CD4 receptor and one of the CXCR4 or CCR5 chemokine co-receptors. There is currently considerable interest in developing novel ligands that can bind to these co-receptors and hence block virus-cell fusion. This article reviews the use of different in silico structure-based and ligand-based virtual screening (VS) tools for the discovery of potential HIV entry inhibitors for the CXCR4 receptor. More specifically, it discusses homology modelling, de novo design, docking, QSAR analyses, pharmacophore modelling, and similarity searches. Results from retrospective VS of a library of known CXCR4 inhibitors taken from the literature and from prospective VS of a combinatorial virtual library are reviewed. The structures of active compounds found by these approaches, as well as CXCR4 inhibitors currently in development, are also discussed. Drug Dev Res 72:95-111, 2011.

Highly SpecIfic and Sensitive Pharmacophore Model for Identifying CXCR4 Antagonists. Comparison with Docking and Shape-Matching Virtual Screening Performance

“…Therefore, we must take this into account when analyzing our results, which show shape-matching scoring functions performing the poorest (AUC values for shape-matching scoring functions approximately random), since we used the isothiourea ligand in the structure as a unique representative shape-matching query. Recent studies have shown that using a consensus query, which can average the essential features of several known high-affinity scaffold families to take into account multiple binding subsite shapes, can highly improve shape-matching VS performance. ,,− …”

Impact of the CXCR4 structure on docking-based virtual screening of HIV entry inhibitors

“…For example, by including receptor backbone flexibility, it is possible to consolidate all the mutation data pertaining to the binding of the cyclam compounds [14]. Techniques that deal with "difficult targets", that is to say targets with multiple binding sites or multiple binding modes, have recently appeared in order to improve the screening performance, such as consensus shape screening [59][60][61].…”

Recent Trends and Future Prospects in Computational GPCR Drug Discovery: From Virtual Screening to Polypharmacology

“…For example, for CXCR4 inhibitors, Wong et al [226] and Pettersson et al [238] have reported binding-mode analyses for bicyclam, monocyclam, and noncyclam compounds [239]. Both agree that none of the dockings into CXCR4 can explain all mutant results by a direct ligandreceptor interaction.…”

“…Hence, other potentially active compounds may be missed. Perez-Nueno et al [92][93][94][95] proposed a spherical harmonic (SH) consensus shape-matching algorithm to help solve this problem. In this approach, the shape of a consensus (or average) pseudomolecule is calculated from the SH representation of each active.…”

“…Regarding CXCR4 entry inhibitors, Perez-Nueno et al [239] built a pharmacophore model for CXCR4 antagonist inhibitors using MOE and Discovery Studio software suites with four families of known actives, namely the AMD3100 analogues, KRH1636 analogues, dipicolil amine zinc(II) complexes, and the diamine derivatives.…”