Design, docking, and evaluation of multiple libraries against multiple targets

We present a general approach to the design, docking, and virtual screening of multiple combinatorial libraries against a family of proteins. The meth od consists of three main stages: docking the scaffold, selecting the best substituents at each site of diversity, and comparing the resultant molecul es within and between the libraries. The core "divide-and-conquer" algorith m 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 l ists of substituents with linear rather than combinatorial time dependence. We have applied our method to three combinatorial libraries and three seri ne proteases: trypsin, chymotrypsin, and elastase. We show that the scaffol d docking procedure, in conjunction with a novel vector-based orientation f ilter, reproduces crystallographic binding modes. In addition, the free-ene rgy-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 macromole cular protease inhibitors. Finally, we show that our method discriminates b etween 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, (C) 2000 Wiley-Liss , Inc.