Using spherical harmonic surface property representations for ligand-based virtual screening

Pérez-Nueno, V. I.; Venkatraman, V.; Mavridis, L.; Clark, T.; Ritchie, D.W.
(2011) Molecular Informatics., 30, 151-159.

Ligand-based virtual screening (VS) techniques have become well established in the drug discovery process. However, despite their relative success, there still exists the problem of how to define the initial query compounds and which of their conformations should be used. Here, we propose a novel shape plus surface property approach using multiple local spherical harmonic (SH) functions. We also investigate the use of shape-based and shape plus property-based consensus SH queries calculated in several different ways. The utility of these approaches is compared using the 40 pharmaceutically relevant targets of the DUD database. Our results show that using a combination of SH-based properties often gives better VS performance than using simple shape-based queries. Shape-based consensus queries also perform well, but we find that explicit 3D shape-property conformations should be retained for highly flexible ligands.

Applying in silico Tools to the Discovery of Novel CXCR4 Inhibitors

Pérez-Nueno, V. I.; Venkatraman, V.; Mavridis, L.; Ritchie, D.W.
(2012) J. Chem. Inf. Model.,52,1948-1961.

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. © 2010 Wiley-Liss, Inc.

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