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Development of a Protein-Ligand Docking Program Based on Global Optimization

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Authors
신웅희
Advisor
석차옥
Major
자연과학대학 화학부
Issue Date
2014-02
Publisher
서울대학교 대학원
Keywords
protein-ligand dockingglobal optimizationvirtual screeningcomputer-aided drug discovery
Description
학위논문 (박사)-- 서울대학교 대학원 : 화학부(물리화학전공), 2014. 2. 석차옥.
Abstract
Protein-ligand docking has become an essential tool for computer-aided drug discovery since docking programs were first developed in 1980s. The goals of docking are to predict 1) the binding mode and 2) the binding affinity of a given protein-ligand complex accurately. Accurate prediction of binding mode requires appropriate sampling of both protein and ligand conformations. Many available docking programs sample ligand structures successfully because ligand has a relatively small number of degrees of freedom. However, a lot of current docking programs treat receptor as a rigid molecule although receptor often adapts its shape to bound ligand because treating receptor flexibility is a very complicated problem. First of all, the large conformational space of receptor is a challenge for typical sampling methods. In addition, current energy functions such as empirical docking score functions or force field-based energy functions do not accurately describe flexible receptor-flexible ligand interactions yet.
In this thesis, the development process of an efficient docking program that treats receptor flexible, called GalaxyDock, is described. A powerful global optimization technique, called conformational space annealing, was employed for simultaneous sampling of the conformational space of protein and ligand. In addition, a new energy function for flexible-receptor docking was designed by combining the AutoDock energy function and a knowledge-based ROTA potential. With these components for sampling and scoring, GalaxyDock shows high performances in the binding pose prediction and virtual screening benchmark tests when compared to other state-of-art docking programs. This result suggests that the GalaxyDock program can provide a firm basis for further method developments and for practical applications to in sillico drug discovery processes.
Language
English
URI
https://hdl.handle.net/10371/125244
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College of Natural Sciences (자연과학대학)Dept. of Chemistry (화학부)Theses (Ph.D. / Sc.D._화학부)
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