Home >> Current Computer - Aided Drug Design, Volume 4, Number 2

How to Efficiently Include Receptor Flexibility During Computational Docking

Authors: May, Andreas; Sieker, Florian; Zacharias, Martin

Source: Current Computer - Aided Drug Design, Volume 4, Number 2, June 2008 , pp. 143-153(11)

Publisher: Bentham Science Publishers

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Abstract:

Target-based drug design uses available 3D structural information of receptor molecules to either dock putative ligand molecules to receptor binding sites or to de-novo design new ligands. In many cases accurate prediction of putative binding geometries requires the appropriate inclusion of conformational flexibility of both the ligand as well as the receptor structure. The problem of appropriate treatment of conformational flexibility during docking is also tightly connected to the improvement of scoring a docked ligand-receptor complex. Highly accurate scoring of a ligand placement is only possible if the complex geometry has been predicted with high precision. Considerable progress has already been achieved in modeling the conformational flexibility of small organic ligands during docking. Although of similar importance, receptor flexibility has not been tackled satisfactorily despite the steady increase in computational power. Especially during virtual screening of large drug-like compound libraries the target structure often is still kept rigid. However, many protein structures undergo local structural changes (side chain or loop motions) as well as global changes in the backbone geometry upon complex formation. In recent years, several promising approaches to efficiently tackle receptor flexibility have been introduced ranging from conformational ensemble methods to explicit inclusion of the most relevant receptor degrees of freedom. Possible applications and future directions on improving flexible docking approaches will be discussed.

More about this publication?
  • Current Computer-Aided Drug Design aims to publish all the latest developments in drug design based on computational techniques. The field of computer-aided drug design has had extensive impact in the area of drug design. Current Computer-Aided Drug Design is an essential journal for all medicinal chemists who wish to be kept informed and up-to-date with all the latest and important developments in computer-aided methodologies and their applications in drug discovery. Each issue contains a series of timely, in-depth reviews written by leaders in the field, covering a range of computational techniques for drug design, screening, ADME studies, etc., providing excellent rationales for drug development.
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