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An Automated Strategy for Binding-Pose Selection and Docking Assessment in Structure-Based Drug Design.
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States.ORCID iD: 0000-0002-4831-3423
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
2016 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 56, no 1, 54-72 p.Article in journal (Refereed) Published
Abstract [en]

Molecular docking is a widely used technique in drug design to predict the binding pose of a candidate compound in a defined therapeutic target. Numerous docking protocols are available, each characterized by different search methods and scoring functions, thus providing variable predictive capability on a same ligand-protein system. To validate a docking protocol, it is necessary to determine a priori the ability to reproduce the experimental binding pose (i.e., by determining the docking accuracy (DA)) in order to select the most appropriate docking procedure and thus estimate the rate of success in docking novel compounds. As common docking programs use generally different root-mean-square deviation (RMSD) formulas, scoring functions, and format results, it is both difficult and time-consuming to consistently determine and compare their predictive capabilities in order to identify the best protocol to use for the target of interest and to extrapolate the binding poses (i.e., best-docked (BD), best-cluster (BC), and best-fit (BF) poses) when applying a given docking program over thousands/millions of molecules during virtual screening. To reduce this difficulty, two new procedures called Clusterizer and DockAccessor have been developed and implemented for use with some common and "free-for-academics" programs such as AutoDock4, AutoDock4(Zn), AutoDock Vina, DOCK, MpSDockZn, PLANTS, and Surflex-Dock to automatically extrapolate BD, BC, and BF poses as well as to perform consistent cluster and DA analyses. Clusterizer and DockAccessor (code available over the Internet) represent two novel tools to collect computationally determined poses and detect the most predictive docking approach. Herein an application to human lysine deacetylase (hKDAC) inhibitors is illustrated.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016. Vol. 56, no 1, 54-72 p.
Keyword [en]
3D QSAR ; Structure Based Drug Design; Molecular Docking; COMBINEr; Clusterizer; DockAccessor; Docking Accuracy; HDAC; KDAC
National Category
Medicinal Chemistry Chemical Sciences Biological Sciences Computer and Information Science
Identifiers
URN: urn:nbn:se:uu:diva-321298DOI: 10.1021/acs.jcim.5b00603PubMedID: 26682916OAI: oai:DiVA.org:uu-321298DiVA: diva2:1095248
Available from: 2017-05-12 Created: 2017-05-12 Last updated: 2017-05-12

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