Survey of public domain software for docking simulations and virtual screening
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Survey of public domain software for docking simulations and virtual screening Jacek Biesiada,1,2 Aleksey Porollo,3 Prakash Velayutham,1 Michal Kouril1 and Jaroslaw Meller1,3,4* 1
Biomedical Informatics, Children’s Hospital Research Foundation, Cincinnati, OH 45229, USA Division of Management and Informatics, Technical University of Silesia, 40-819 Katowice, Poland 3 Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45226, USA 4 Department of Informatics, Nicholas Copernicus University, 87-100 Torun, Poland *Correspondence to: Tel: þ1 513 558 1958; E-mail: [email protected] 2
Date received (in revised form): 14th May 2011
Abstract Progress in functional genomics and structural studies on biological macromolecules are generating a growing number of potential targets for therapeutics, adding to the importance of computational approaches for small molecule docking and virtual screening of candidate compounds. In this review, recent improvements in several public domain packages that are widely used in the context of drug development, including DOCK, AutoDock, AutoDock Vina and Screening for Ligands by Induced-fit Docking Efficiently (SLIDE) are surveyed. The authors also survey methods for the analysis and visualisation of docking simulations, as an important step in the overall assessment of the results. In order to illustrate the performance and limitations of current docking programs, the authors used the National Center for Toxicological Research (NCTR) oestrogen receptor benchmark set of 232 oestrogenic compounds with experimentally measured strength of binding to oestrogen receptor alpha. The methods tested here yielded a correlation coefficient of up to 0.6 between the predicted and observed binding affinities for active compounds in this benchmark. Keywords: drug discovery, small molecule docking, virtual screening, docking packages, visualisation of docking poses, oestrogen receptor, oestrogen activity prediction, SAR
Introduction Docking simulations and virtual screening are being routinely used in drug design, enabling rapid identification of hits and lead compounds.1 – 3 The goal of docking simulations is to determine the binding mode (bound conformation) and the strength of binding (binding affinity) between a ligand, which is typically assumed to be a small molecule, and a macromolecular receptor, such as a protein.1,3,4 Given a resolved or modelled structure of a target receptor, virtual screening involves performing docking simulations for a large number of candidate compounds in order to identify putative leads.2,5,6 These candidates can subsequently be characterised and validated by empirical binding
and activity assays, and by assessing their toxicity, pharmacokinetics and other properties for further drug development.7 – 9 Many methods for molecular docking and virtual screening have been developed to date, including AutoDock,10,11 DOCK,12 – 14 Flex,15 Glide,16 GOLD,17 RosettaDock,18 SLIDE19,20 and Surflex.21 These methods introduce various ap
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