A minimalist approach to fragment-based ligand design using common rings and linkers: application to kinase inhibitors.
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.
Vertex Pharmaceuticals Inc., Cambridge, Massachusetts 02139-4242, USA. alex_aronov@vrtx.com
Alex M
AM
Aronov
Guy W
GW
Bemis
D000465:Algorithms; D001549:Benzamides; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D051357:Cyclin-Dependent Kinase 2; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry; D015195:Drug Design; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry; D011451:Prostaglandin-Endoperoxide Synthases; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000737:chemistry; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D001549:Benzamides; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008024:Ligands; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2