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

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

doi:10.1016/j.bmcl.2007.04.110

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

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

Chemistry

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	3880-3885
Number of pages	6
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	17
Issue number	14
DOIs	https://doi.org/10.1016/j.bmcl.2007.04.110
Publication status	Published - 15 Jul 2007

Keywords

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

Access to Document

10.1016/j.bmcl.2007.04.110

Cite this

Richardson, C. M., Nunns, C. L., Williamson, D. S., Parratt, M. J., Dokurno, P., Howes, R., Borgognoni, J., Drysdale, M. J., Finch, H., Hubbard, R. E., Jackson, P. S., Kierstan, P., Lentzen, G., Moore, J. D., Murray, J. B., Simmonite, H., Surgenor, A. E., & Torrance, C. J. (2007). Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping. Bioorganic & Medicinal Chemistry Letters, 17(14), 3880-3885. https://doi.org/10.1016/j.bmcl.2007.04.110

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

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.",

keywords = "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",

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

year = "2007",

month = jul,

day = "15",

doi = "10.1016/j.bmcl.2007.04.110",

language = "English",

volume = "17",

pages = "3880--3885",

journal = "Bioorganic & Medicinal Chemistry Letters",

issn = "0960-894X",

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Richardson, CM, Nunns, CL, Williamson, DS, Parratt, MJ, Dokurno, P, Howes, R, Borgognoni, J, Drysdale, MJ, Finch, H, Hubbard, RE, Jackson, PS, Kierstan, P, Lentzen, G, Moore, JD, Murray, JB, Simmonite, H, Surgenor, AE & Torrance, CJ 2007, 'Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping', Bioorganic & Medicinal Chemistry Letters, vol. 17, no. 14, pp. 3880-3885. https://doi.org/10.1016/j.bmcl.2007.04.110

TY - JOUR

T1 - Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping

AU - Richardson, Christine M.

AU - Nunns, Claire L.

AU - Williamson, Douglas S.

AU - Parratt, Martin J.

AU - Dokurno, Pawel

AU - Howes, Rob

AU - Borgognoni, Jenifer

AU - Drysdale, Martin J.

AU - Finch, Harry

AU - Hubbard, Roderick E.

AU - Jackson, Philip S.

AU - Kierstan, Peter

AU - Lentzen, Georg

AU - Moore, Jonathan D.

AU - Murray, James B.

AU - Simmonite, Heather

AU - Surgenor, Allan E.

AU - Torrance, Christopher J.

PY - 2007/7/15

Y1 - 2007/7/15

N2 - 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.

AB - 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.

KW - virtual screening

KW - docking

KW - CDK2

KW - cyclin dependent kinase

KW - X-ray crystallography

KW - structure-guided drug design

KW - fragment based

KW - KINASE INHIBITORS

KW - PROMISCUOUS INHIBITORS

KW - CHEMICAL LIBRARIES

KW - HOMOLOGY MODELS

KW - PROTEIN-KINASES

KW - DOCKING

KW - DESIGN

KW - IDENTIFICATION

KW - COMMON

U2 - 10.1016/j.bmcl.2007.04.110

DO - 10.1016/j.bmcl.2007.04.110

M3 - Article

SN - 0960-894X

VL - 17

SP - 3880

EP - 3885

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 14

ER -