Active-site-directed 3D database searching: Pharmacophore extraction and validation of hits

被引:24
作者
Clark, DE [1 ]
Westhead, DR [1 ]
Sykes, RA [1 ]
Murray, CW [1 ]
机构
[1] PROTEUS MOL DESIGN LTD, MACCLESFIELD SK11 OJL, CHESHIRE, ENGLAND
关键词
drug design; lead generation; thrombin inhibitors; scoring function;
D O I
10.1007/BF00124472
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
Two new computational tools, PRO_PHARMEX and PRO_SCOPE, for use in active-site-directed searching of 3D databases are described. PRO_PHARMEX is a flexible, graphics-based program facilitating the extraction of pharmacophores from the active site of a target macromolecule. These pharmacophores can then be used to search a variety of databases for novel lead compounds. Such searches can often generate many 'hits' of varying quality. To aid the user in setting priorities for purchase, synthesis or testing, PRO_SCOPE can be used to dock molecules rapidly back into the active site and to assign them a score using an empirical scoring function correlated to the free energy of binding. To illustrate how these tools can add value to existing 3D database software, their use in the design of novel thrombin inhibitors is described.
引用
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页码:397 / 416
页数:20
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