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Systematic exploration of multiple drug binding sites
University of Pécs, Medical School, Department of Pharmacology and Pharmacotherapy; Eötvös Loránd University, Department of Biochemistry.
University of Pécs, Center for Neuroscience, MTA NAP -B Molecular Neuroendocrinology Group, Institute of Physiology.
University of Szeged, Chemistry Doctoral School.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
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2017 (English)In: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 9, no 65Article in journal (Refereed) Published
Abstract [en]

Background: Targets with multiple (prerequisite or allosteric) binding sites have an increasing importance in drug design. Experimental determination of atomic resolution structures of ligands weakly bound to multiple binding sites is often challenging. Blind docking has been widely used for fast mapping of the entire target surface for multiple binding sites. Reliability of blind docking is limited by approximations of hydration models, simplified handling of molecular flexibility, and imperfect search algorithms.

Results: To overcome such limitations, the present study introduces Wrap 'n' Shake (WnS), an atomic resolution method that systematically "wraps" the entire target into a monolayer of ligand molecules. Functional binding sites are extracted by a rapid molecular dynamics shaker. WnS is tested on biologically important systems such as mitogenactivated protein, tyrosine-protein kinases, key players of cellular signaling, and farnesyl pyrophosphate synthase, a target of antitumor agents.

Place, publisher, year, edition, pages
2017. Vol. 9, no 65
Keywords [en]
Peptide, Search, Pocket, Pharmacodynamics, Water, Interaction, Structure, Complex, Dissociation, Flexibility
National Category
Computer Sciences Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-339761DOI: 10.1186/s13321-017-0255-6ISI: 000418814800001OAI: oai:DiVA.org:uu-339761DiVA, id: diva2:1179843
Available from: 2018-02-02 Created: 2018-02-02 Last updated: 2018-02-02Bibliographically approved

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