Conformational Flexibility Models for the Receptor in Structure Based Drug Design

Authors: Teodoro, M. L.; Kavraki, L. E.

Source: Current Pharmaceutical Design, Volume 9, Number 20, August 2003 , pp. 1635-1648(14)

Publisher: Bentham Science Publishers

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Abstract:

The problem of incorporating receptor flexibility in routine in silico screening of databases of small chemical compounds for the purposes of structure based drug design is still an unsolved problem. The main reason behind this difficulty is the large number of degrees of freedom that have to be considered to represent receptor flexibility. In this paper we review protein flexibility models that have been developed to limit the number of additional search parameters. These models can be roughly divided into five different categories. These are a) use of soft receptors which relax energetic penalties due to steric clashes, b) selection of a few critical degrees of freedom in the receptor binding site, c) use of multiple receptor structures either individually or by combining them using an averaging scheme, d) use of modified molecular simulation methods, and e) use of collective degrees of freedom as a new basis of representation for protein flexibility. All these flexible receptor models strive to balance an improvement in the accuracy of the binding predictions with an increase in computational cost. In addition, other challenges such as the development of accurate solvation models and scoring functions make the receptor flexibility problem even harder.

Keywords: Conformational Flexibility Models

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1381612033454595

Affiliations: 1: Department of Computer Science, Rice University, 6100 Main St, MS 132, P.O. Box 1892, Houston, TX 77251-1892, USA.

Publication date: 2003-08-01

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Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.

Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

Conformational Flexibility Models for the Receptor in Structure Based Drug Design

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