SPROUT - A PROGRAM FOR STRUCTURE GENERATION

被引:144
作者
GILLET, V
JOHNSON, AP
MATA, P
SIKE, S
WILLIAMS, P
机构
[1] UNIV LEEDS, SCH CHEM, LEEDS LS2 9JT, W YORKSHIRE, ENGLAND
[2] UNIV NOVA LISBOA, FAC CIENCIAS & TECNOL, DEPT QUIM, MONTE DE CAPARICA, PORTUGAL
关键词
ARTIFICIAL INTELLIGENCE; DENOVO DESIGN; MOLECULE DESIGN; ENZYME INHIBITORS;
D O I
10.1007/BF00126441
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
SPROUT is a new computer program for constrained structure generation that is designed to generate molecules for a range of applications in molecular recognition. It uses artificial intelligence techniques to moderate the combinatorial explosion that is inherent in structure generation. The program is presented here for the design of enzyme inhibitors. Structure generation is divided into two phases: (i) primary structure generation to produce molecular graphs to fit the steric constraints; and (ii) secondary structure generation which is the process of introducing appropriate functionality to the graphs to produce molecules that satisfy the secondary constraints, e.g., electrostatics and hydrophobicity. Primary structure generation has been tested on two enzyme receptor sites; the p-amidino-phenyl-pyruvate binding site of trypsin and the acetyl pepstatin binding site of HIV-1 protease. The program successfully generates structures that resemble known substrates and, more importantly, the predictive power of the program has been demonstrated by its ability to suggest novel structures.
引用
收藏
页码:127 / 153
页数:27
相关论文
共 32 条
[1]   THE COMPUTER-PROGRAM LUDI - A NEW METHOD FOR THE DENOVO DESIGN OF ENZYME-INHIBITORS [J].
BOHM, HJ .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 1992, 6 (01) :61-78
[2]   MOLECULAR MODELING SOFTWARE AND METHODS FOR MEDICINAL CHEMISTRY .2. [J].
COHEN, NC ;
BLANEY, JM ;
HUMBLET, C ;
GUND, P ;
BARRY, DC .
JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (03) :883-894
[3]   AUTOMATED SITE-DIRECTED DRUG DESIGN - A GENERAL ALGORITHM FOR KNOWLEDGE ACQUISITION ABOUT HYDROGEN-BONDING REGIONS AT PROTEIN SURFACES [J].
DANZIGER, DJ ;
DEAN, PM .
PROCEEDINGS OF THE ROYAL SOCIETY SERIES B-BIOLOGICAL SCIENCES, 1989, 236 (1283) :101-+
[4]   USING SHAPE COMPLEMENTARITY AS AN INITIAL SCREEN IN DESIGNING LIGANDS FOR A RECEPTOR-BINDING SITE OF KNOWN 3-DIMENSIONAL STRUCTURE [J].
DESJARLAIS, RL ;
SHERIDAN, RP ;
SEIBEL, GL ;
DIXON, JS ;
KUNTZ, ID ;
VENKATARAGHAVAN, R .
JOURNAL OF MEDICINAL CHEMISTRY, 1988, 31 (04) :722-729
[6]  
FITZGERALD PMD, 1990, J BIOL CHEM, V265, P14209
[7]  
GILLET VJ, UNPUB
[9]   AUTOMATED DOCKING OF SUBSTRATES TO PROTEINS BY SIMULATED ANNEALING [J].
GOODSELL, DS ;
OLSON, AJ .
PROTEINS-STRUCTURE FUNCTION AND GENETICS, 1990, 8 (03) :195-202
[10]   PROBING THE CONFORMATIONAL SPACE AVAILABLE TO INHIBITORS IN THE THERMOLYSIN ACTIVE-SITE USING MONTE-CARLO ENERGY MINIMIZATION TECHNIQUES [J].
GUIDA, WC ;
BOHACEK, RS ;
ERION, MD .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 1992, 13 (02) :214-228