Predicting the Accuracy of Protein-Ligand Docking on Homology Models

被引:73
作者
Bordogna, Annalisa [1 ]
Pandini, Alessandro [2 ]
Bonati, Laura [1 ]
机构
[1] Univ Milano Bicocca, Dipartimento Sci Ambiente & Terr, Milan, Italy
[2] Natl Inst Med Res, Div Math Biol, London NW7 1AA, England
基金
美国国家卫生研究院;
关键词
molecular docking; drug discovery; homology modeling; model quality assessment; model quality indices; QUALITY ASSESSMENT; DRUG DISCOVERY; MOLECULAR DOCKING; SEQUENCE; CONFORMATIONS; FLEXIBILITY; ALIGNMENT; DATABASE; SERVER;
D O I
10.1002/jcc.21601
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Ligand-protein docking is increasingly used in Drug Discovery. The initial limitations imposed by a reduced availability of target protein structures have been overcome by the use of theoretical models, especially those derived by homology modeling techniques. While this greatly extended the use of docking simulations, it also introduced the need for general and robust criteria to estimate the reliability of docking results given the model quality. To this end, a large-scale experiment was performed on a diverse set including experimental structures and homology models for a group of representative ligand-protein complexes. A wide spectrum of model quality was sampled using templates at different evolutionary distances and different strategies for target-template alignment and modeling. The obtained models were scored by a selection of the most used model quality indices. The binding geometries were generated using AutoDock, one of the most common docking programs. An important result of this study is that indeed quantitative and robust correlations exist between the accuracy of docking results and the model quality, especially in the binding site. Moreover, state-of-the-art indices for model quality assessment are already an effective tool for an a priori prediction of the accuracy of docking experiments in the context of groups of proteins with conserved structural characteristics. (C) 2010 Wiley Periodicals, Inc. J Comput Chem 32: 81-98, 2011
引用
收藏
页码:81 / 98
页数:18
相关论文
共 56 条
[1]   Gapped BLAST and PSI-BLAST: a new generation of protein database search programs [J].
Altschul, SF ;
Madden, TL ;
Schaffer, AA ;
Zhang, JH ;
Zhang, Z ;
Miller, W ;
Lipman, DJ .
NUCLEIC ACIDS RESEARCH, 1997, 25 (17) :3389-3402
[2]  
Arnold Konstantin, 2009, Journal of Structural and Functional Genomics, V10, P1, DOI 10.1007/s10969-008-9048-5
[3]   Managing protein flexibility in docking and its applications [J].
B-Rao, Chandrika ;
Subramanian, Jyothi ;
Sharma, Somesh D. .
DRUG DISCOVERY TODAY, 2009, 14 (7-8) :394-400
[4]   Automated server predictions in CASP7 [J].
Battey, James N. D. ;
Kopp, Jurgen ;
Bordoli, Lorenza ;
Read, Randy J. ;
Clarke, Neil D. ;
Schwede, Torsten .
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2007, 69 :68-82
[5]   The Protein Data Bank [J].
Berman, HM ;
Westbrook, J ;
Feng, Z ;
Gilliland, G ;
Bhat, TN ;
Weissig, H ;
Shindyalov, IN ;
Bourne, PE .
NUCLEIC ACIDS RESEARCH, 2000, 28 (01) :235-242
[6]   Evaluating protein structures determined by structural genomics consortia [J].
Bhattacharya, Aneerban ;
Tejero, Roberto ;
Montelione, Gaetano T. .
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2007, 66 (04) :778-795
[7]   Homology modeling in drug discovery: current trends and applications [J].
Cavasotto, Claudio N. ;
Phatak, Sharangdhar S. .
DRUG DISCOVERY TODAY, 2009, 14 (13-14) :676-683
[8]  
Chapman B., 2000, ACM SIGBIO NEWSLETT, V20, P15
[9]   THE RELATION BETWEEN THE DIVERGENCE OF SEQUENCE AND STRUCTURE IN PROTEINS [J].
CHOTHIA, C ;
LESK, AM .
EMBO JOURNAL, 1986, 5 (04) :823-826
[10]   Relationship between multiple sequence alignments and quality of protein comparative models [J].
Cozzetto, D ;
Tramontano, A .
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2005, 58 (01) :151-157