DocumentCode :
1299427
Title :
Toward a Robust Search Method for the Protein-Drug Docking Problem
Author :
Sadjad, Bashir S. ; Zsoldos, Zsolt
Author_Institution :
Sch. of Comput. Sci., Univ. of Waterloo, Waterloo, ON, Canada
Volume :
8
Issue :
4
fYear :
2011
Firstpage :
1120
Lastpage :
1133
Abstract :
Predicting the binding mode(s) of a drug molecule to a target receptor is pivotal in structure-based rational drug design. In contrast to most approaches to solve this problem, the idea in this paper is to analyze the search problem from a computational perspective. By building on top of an existing docking tool, new methods are proposed and relevant computational results are proven. These methods and results are applicable for other place-and-join frameworks as well. A fast approximation scheme for the docking of rigid fragments is described that guarantees certain geometric approximation factors. It is also demonstrated that this can be translated into an energy approximation for simple scoring functions. A polynomial time algorithm is developed for the matching phase of the docked rigid fragments. It is demonstrated that the generic matching problem is NP-hard. At the same time, the optimality of the proposed algorithm is proven under certain scoring function conditions. The matching results are also applicable for some of the fragment-based de novo design methods. On the practical side, the proposed method is tested on 829 complexes from the PDB. The results show that the closest predicted pose to the native structure has the average RMS deviation of 1.06 Å.
Keywords :
bioinformatics; computational complexity; drugs; molecular biophysics; proteins; search problems; NP hard generic matching problem; docked rigid fragment matching phase; docking tool; drug molecule binding mode prediction; energy approximation; polynomial time algorithm; protein-drug docking problem; rigid fragment docking approximation scheme; scoring functions; search method; structure based rational drug design; target receptor; Accuracy; Approximation methods; Bioinformatics; Cavity resonators; Computational biology; Drugs; Proteins; Life and medical sciences; and object representations; bioinformatics (genome or protein) databases.; biology and genetics; curve; geometrical problems and computations; solid; surface; Algorithms; Binding Sites; Computational Biology; Databases, Genetic; Drug Discovery; Models, Molecular; Pharmaceutical Preparations; Protein Binding; Proteins;
fLanguage :
English
Journal_Title :
Computational Biology and Bioinformatics, IEEE/ACM Transactions on
Publisher :
ieee
ISSN :
1545-5963
Type :
jour
DOI :
10.1109/TCBB.2010.70
Filename :
5551120
Link To Document :
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