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Design, docking, and evaluation of multiple libraries against multiple targets
Author(s) -
Lamb Michelle L.,
Burdick Keith W.,
Toba Samuel,
Young Malin M.,
Skillman A. Geoffrey,
Zou Xiaoqin,
Arnold James R.,
Kuntz Irwin D.
Publication year - 2001
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/1097-0134(20010215)42:3<296::aid-prot20>3.0.co;2-f
Subject(s) - docking (animal) , virtual screening , computational biology , computer science , chemistry , divide and conquer algorithms , protein–ligand docking , combinatorial chemistry , drug discovery , algorithm , biology , biochemistry , medicine , nursing
We present a general approach to the design, docking, and virtual screening of multiple combinatorial libraries against a family of proteins. The method consists of three main stages: docking the scaffold, selecting the best substituents at each site of diversity, and comparing the resultant molecules within and between the libraries. The core “divide‐and‐conquer” algorithm for side‐chain selection, developed from an earlier version (Sun et al., J Comp Aided Mol Design 1998;12:597–604), provides a way to explore large lists of substituents with linear rather than combinatorial time dependence. We have applied our method to three combinatorial libraries and three serine proteases: trypsin, chymotrypsin, and elastase. We show that the scaffold docking procedure, in conjunction with a novel vector‐based orientation filter, reproduces crystallographic binding modes. In addition, the free‐energy‐based scoring procedure (Zou et al., J Am Chem Soc 1999;121:8033–8043) is able to reproduce experimental binding data for P 1 mutants of macromolecular protease inhibitors. Finally, we show that our method discriminates between a peptide library and virtual libraries built on benzodiazepine and tetrahydroisoquinolinone scaffolds. Implications of the docking results for library design are explored. Proteins 2001;42:296–318. © 2000 Wiley‐Liss, Inc.