Title: Approaches to the Description and Prediction of the Binding Affinity of Small-Molecule Ligands to Macromolecular Receptors
Abstract: Angewandte Chemie International EditionVolume 41, Issue 15 p. 2644-2676 Review Approaches to the Description and Prediction of the Binding Affinity of Small-Molecule Ligands to Macromolecular Receptors Holger Gohlke Dr., Holger Gohlke Dr. Institut für Pharmazeutische Chemie Philipps-Universität Marburg Marbacher Weg 6, 35032 Marburg (Germany) Fax: (+49) 6421-282-8994Search for more papers by this authorGerhard Klebe Prof. Dr., Gerhard Klebe Prof. Dr. [email protected] Institut für Pharmazeutische Chemie Philipps-Universität Marburg Marbacher Weg 6, 35032 Marburg (Germany) Fax: (+49) 6421-282-8994Search for more papers by this author Holger Gohlke Dr., Holger Gohlke Dr. Institut für Pharmazeutische Chemie Philipps-Universität Marburg Marbacher Weg 6, 35032 Marburg (Germany) Fax: (+49) 6421-282-8994Search for more papers by this authorGerhard Klebe Prof. Dr., Gerhard Klebe Prof. Dr. [email protected] Institut für Pharmazeutische Chemie Philipps-Universität Marburg Marbacher Weg 6, 35032 Marburg (Germany) Fax: (+49) 6421-282-8994Search for more papers by this author First published: 02 August 2002 https://doi.org/10.1002/1521-3773(20020802)41:15<2644::AID-ANIE2644>3.0.CO;2-OCitations: 607Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract Biological activity at the molecular level involves the binding of a small-molecule ligand to a macromolecular receptor, usually a protein, in aqueous solution (see scheme). Enthalpic and entropic contributions arising from inter- and intramolecular effects determine the affinity of both binding partners towards each other. Affinity as a key element in life sciences—how well is this quantity understood today? Abstract The influence of a xenobiotic compound on an organism is usually summarized by the expression biological activity. If a controlled, therapeutically relevant, and regulatory action is observed the compound has potential as a drug, otherwise its toxicity on the biological system is of interest. However, what do we understand by the biological activity? In principle, the overall effect on an organism has to be considered. However, because of the complexity of the interrelated processes involved, as a simplification primarily the “main action” on the organism is taken into consideration. On the molecular level, biological activity corresponds to the binding of a (low-molecular weight) compound to a macromolecular receptor, usually a protein. Enzymatic reactions or signal-transduction cascades are thereby influenced with respect to their function for the organism. We regard this binding as a process under equilibrium conditions; thus, binding can be described as an association or dissociation process. Accordingly, biological activity is expressed as the affinity of both partners for each other, as a thermodynamic equilibrium quantity. How well do we understand these terms and how well are they theoretically predictable today? The holy grail of rational drug design is the prediction of the biological activity of a compound. The processes involving ligand binding are extremely complicated, both ligand and protein are flexible molecules, and the energy inventory between the bound and unbound states must be considered in aqueous solution. How sophisticated and reliable are our experimental approaches to obtaining the necessary insight? The present review summarizes our current understanding of the binding affinity of a small-molecule ligand to a protein. Both theoretical and empirical approaches for predicting binding affinity, starting from the three-dimensional structure of a protein–ligand complex, will be described and compared. Experimental methods, primarily microcalorimetry, will be discussed. As a perspective, our own knowledge-based approach towards affinity prediction and experimental data on factorizing binding contributions to protein–ligand binding will be presented. Citing Literature Volume41, Issue15August 2, 2002Pages 2644-2676 RelatedInformation
Publication Year: 2002
Publication Date: 2002-08-02
Language: en
Type: review
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 763
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