Q-DockLHM: Low-Resolution Refinement for Ligand Comparative Modeling

被引:20
作者
Brylinski, Michal [1 ]
Skolnick, Jeffrey [1 ]
机构
[1] Georgia Inst Technol, Sch Biol, Ctr Study Syst Biol, Atlanta, GA 30318 USA
基金
美国国家卫生研究院;
关键词
Q-dock; ligand docking; homology modeling; low-resolution modeling; threading; SIDE-CHAIN FLEXIBILITY; MOLECULAR-DOCKING; STRUCTURE PREDICTION; SCORING FUNCTION; PROTEIN FLEXIBILITY; GENETIC ALGORITHM; BINDING; RECOGNITION; PROGRAMS; VALIDATION;
D O I
10.1002/jcc.21395
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The success of ligand docking calculations typically depends on the quality of the receptor structure. Given improvements in protein structure prediction approaches, approximate protein models now can be routinely obtained for the majority of gene products in a given proteome. Structure-based virtual screening of large combinatorial libraries of lead Candidates against theoretically modeled receptor Structures requires fast and reliable docking, techniques Capable of dealing with structural inaccuracies in protein models. Here, we present Q-Dock(LHM), a method for low-resolution refinement of binding poses provided by FINDSITELHM, a ligand homology modeling approach. We compare its performance to that of classical ligand docking approaches in ligand docking against a representative set of experimental (both holo and apo) as well as theoretically modeled receptor Structures. Docking benchmarks reveal that unlike all-atom docking, Q-Dock(LHM) exhibits the desired tolerance to the receptor's Structure deformation. Our results Suggest that the use of an evolution-based approach to ligand homology modeling followed by fast low-resolution refinement is capable of achieving satisfactory performance in ligand-binding pose prediction with promising applicability to proteome-scale applications. (C) 2009 Wiley Periodicals. Inc. J Comput Chem 31: 1093-1105, 2010
引用
收藏
页码:1093 / 1105
页数:13
相关论文
共 79 条
[11]   An overview of structural genomics [J].
Burley, SK .
NATURE STRUCTURAL BIOLOGY, 2000, 7 (Suppl 11) :932-934
[12]   Protein flexibility in ligand docking and virtual screening to protein kinases [J].
Cavasotto, CN ;
Abagyan, RA .
JOURNAL OF MOLECULAR BIOLOGY, 2004, 337 (01) :209-225
[13]   Evaluating molecular-docking methods for pose prediction and enrichment factors [J].
Chen, HM ;
Lyne, PD ;
Giordanetto, F ;
Lovell, T ;
Li, J .
JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2006, 46 (01) :401-415
[14]   Comparing protein-ligand docking programs is difficult [J].
Cole, JC ;
Murray, CW ;
Nissink, JWM ;
Taylor, RD ;
Taylor, R .
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2005, 60 (03) :325-332
[15]   Docking ligands into flexible and solvated macromolecules. 1. Development and validation of FITTED 1.0 [J].
Corbeil, Christopher R. ;
Englebienne, Pablo ;
Moitessier, Nicolas .
JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2007, 47 (02) :435-449
[16]   Comparison of automated docking programs as virtual screening tools [J].
Cummings, MD ;
DesJarlais, RL ;
Gibbs, AC ;
Mohan, V ;
Jaeger, EP .
JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (04) :962-976
[17]   ROSETTALIGAND Docking with Full Ligand and Receptor Flexibility [J].
Davis, Ian W. ;
Baker, David .
JOURNAL OF MOLECULAR BIOLOGY, 2009, 385 (02) :381-392
[18]   Effects of ligand binding on the internal dynamics of maltose-binding protein [J].
Döring, K ;
Surrey, T ;
Nollert, P ;
Jähnig, F .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1999, 266 (02) :477-483
[19]   Lessons in molecular recognition: The effects of ligand and protein flexibility on molecular docking accuracy [J].
Erickson, JA ;
Jalaie, M ;
Robertson, DH ;
Lewis, RA ;
Vieth, M .
JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (01) :45-55
[20]   DOCK 4.0: Search strategies for automated molecular docking of flexible molecule databases [J].
Ewing, TJA ;
Makino, S ;
Skillman, AG ;
Kuntz, ID .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2001, 15 (05) :411-428