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Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping

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Published copy (DOI)

Author(s)

  • Christine M. Richardson
  • Claire L. Nunns
  • Douglas S. Williamson
  • Martin J. Parratt
  • Pawel Dokurno
  • Rob Howes
  • Jenifer Borgognoni
  • Martin J. Drysdale
  • Harry Finch
  • Roderick E. Hubbard
  • Philip S. Jackson
  • Peter Kierstan
  • Georg Lentzen
  • Jonathan D. Moore
  • James B. Murray
  • Heather Simmonite
  • Allan E. Surgenor
  • Christopher J. Torrance

Department/unit(s)

Publication details

JournalBioorganic & Medicinal Chemistry Letters
DatePublished - 15 Jul 2007
Issue number14
Volume17
Number of pages6
Pages (from-to)3880-3885
Original languageEnglish

Abstract

Virtual screening against a pCDK2/cyclin A crystal structure led to the identification of a potent and novel CDK2 inhibitor, which exhibited an unusual mode of interaction with the kinase binding motif. With the aid of X-ray crystallography and modelling, a medicinal chemistry strategy was implemented to probe the interactions seen in the crystal structure and to establish SAR. A fragment-based approach was also considered but a different, more conventional, binding mode was observed. Compound selectivity against GSK-3 beta was improved using a rational design strategy, with crystallographic verification of the CDK2 binding mode. (C) 2007 Elsevier Ltd. All rights reserved.

    Research areas

  • virtual screening, docking, CDK2, cyclin dependent kinase, X-ray crystallography, structure-guided drug design, fragment based, KINASE INHIBITORS, PROMISCUOUS INHIBITORS, CHEMICAL LIBRARIES, HOMOLOGY MODELS, PROTEIN-KINASES, DOCKING, DESIGN, IDENTIFICATION, COMMON

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