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A minimalist approach to fragment‐based ligand design using common rings and linkers: Application to kinase inhibitors
Author(s) -
Aronov Alex M.,
Bemis Guy W.
Publication year - 2004
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/prot.20173
Subject(s) - linker , scaffold , ligand (biochemistry) , chemistry , ligand efficiency , fragment (logic) , computational biology , combinatorial chemistry , ring (chemistry) , stereochemistry , computer science , biology , biochemistry , algorithm , database , programming language , receptor , organic chemistry
Abstract We present a novel method for stepwise scaffold assembly that integrates fragment‐by‐fragment ligand design approaches with high‐throughput virtual library screening (COREGEN). As an extension of our earlier studies of common features present in drug molecules, we investigate the hypothesis that most pharmaceutically interesting ligands can be expressed in terms of the ring–linker frameworks that comprise them. Analysis of 119 published kinase inhibitors from at least 18 different targets illustrates that a basis set of 4 rings and 8 linkers is sufficient to describe approximately 90% of ring and linker occurrences, respectively. A similar result was derived from a larger set of approximately 40,000 kinase inhibitors from curated patents. A method for ring–linker‐based assembly of scaffold libraries that uses experimental information to guide the placement of anchor fragments is validated using a set of reported kinase inhibitors of Bcr‐Abl, Cdk2, and Src. In every case, the predominant structural motif of reported ligand cores is reproduced and variations are suggested. To underscore generality of this approach, a novel scaffold for a cyclooxygenase‐2 (COX‐2) selective ligand is proposed. Proteins 2004. © 2004 Wiley‐Liss, Inc.