Virtual screening of the SAMPL4 blinded HIV integrase inhibitors dataset.
Several combinations of docking software and scoring functions were evaluated for their ability to predict the binding of a dataset of potential HIV integrase inhibitors. We found that different docking software were appropriate for each one of the three binding sites considered (LEDGF, Y3 and fragment sites), and the most suitable two docking protocols, involving Glide SP and Gold ChemScore, were selected using a training set of compounds identified from the structural data available. These protocols could successfully predict respectively 20.0 and 23.6 % of the HIV integrase binders, all of them being present in the LEDGF site. When a different analysis of the results was carried out by removing all alternate isomers of binders from the set, our predictions were dramatically improved, with an overall ROC AUC of 0.73 and enrichment factor at 10 % of 2.89 for the prediction obtained using Gold ChemScore. This study highlighted the ability of the selected docking protocols to correctly position in most cases the ortho-alkoxy-carboxylate core functional group of the ligands in the corresponding binding site, but also their difficulties to correctly rank the docking poses.
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Centre de Recherche de Gif-sur-Yvette, Labex LERMIT, 1 Avenue de la Terrasse, 91198, Gif-sur-Yvette, France.
Claire
C
Colas
Bogdan I
BI
Iorga
D001665:Binding Sites; D017076:Computer-Aided Design; D030562:Databases, Protein; D015195:Drug Design; D006678:HIV / Q000201:enzymology*; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology / Q000821:virology; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D012984:Software
D019428:HIV Integrase Inhibitors; D008024:Ligands; D019427:HIV Integrase