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Recipes for the Selection of Experimental Protein Conformations for Virtual Screening Manuel Rueda,

Summary: Recipes for the Selection of Experimental Protein Conformations for Virtual Screening
Manuel Rueda,
Giovanni Bottegoni,
and Ruben Abagyan*,,
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, Mail
TPC-28, La Jolla, California 92037, Department of Drug Discovery and Development (D3), Istituto Italiano di
Tecnologia, via Morego n. 30, Genova, 16163, Italy, and Molsoft, LLC, 3366 North Torrey Pines Court, Suite
300, La Jolla, California 92037
Received October 9, 2009
The use of multiple X-ray protein structures has been reported to be an efficient alternative for the
representation of the binding pocket flexibility needed for accurate small molecules docking. However, the
docking performance of the individual single conformations varies widely, and adding certain conformations
to an ensemble is even counterproductive. Here we used a very large and diverse benchmark of 1068 X-ray
protein conformations of 99 therapeutically relevant proteins, first, to compare the performance of the ensemble
and single-conformation docking and, second, to find the properties of the best-performing conformers that
can be used to select a smaller set of conformers for ensemble docking. The conformer selection has been
validated through retrospective virtual screening experiments aimed at separating known ligand binders
from decoys. We found that the conformers cocrystallized with the largest ligands displayed high selectivity
for binders, and when combined in ensembles they consistently provided better results than randomly chosen
protein conformations. The use of ensembles encompassing between 3 and 5 experimental conformations


Source: Abagyan, Ruben - School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego


Collections: Biology and Medicine