title: Design, docking, and evaluation of multiple libraries against multiple targets.
abstract: 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 P1 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.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, California, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Lamb
authors.forename: K W
authors.initials: KW
authors.lastname: Burdick
authors.forename: S
authors.initials: S
authors.lastname: Toba
authors.forename: M M
authors.initials: MM
authors.lastname: Young
authors.forename: A G
authors.initials: AG
authors.lastname: Skillman
authors.forename: X
authors.initials: X
authors.lastname: Zou
authors.forename: J R
authors.initials: JR
authors.lastname: Arnold
authors.forename: I D
authors.initials: ID
authors.lastname: Kuntz
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009154:Mutation; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D015203:Reproducibility of Results; D014357:Trypsin / Q000737:chemistry / Q000187:drug effects
chemical_list: D000596:Amino Acids; D004791:Enzyme Inhibitors; D019151:Peptide Library; D010455:Peptides; D002918:Chymotrypsin; D014357:Trypsin