title: Discovery of a novel family of CDK inhibitors with the program LIDAEUS: structural basis for ligand-induced disordering of the activation loop.
abstract: A family of 4-heteroaryl-2-amino-pyrimidine CDK2 inhibitor lead compounds was discovered with the new database-mining program LIDAEUS through in silico screening. Four compounds with IC(50) values ranging from 17 to 0.9 microM were selected for X-ray crystal analysis. Two distinct binding modes are observed, one of which resembles the hydrogen bonding pattern of bound ATP. In the second binding mode, the ligands trigger a conformational change in the activation T loop by inducing movement of Lys(33) and Asp(145) side chains. The family of molecules discovered provides an excellent starting point for the design and synthesis of tight binding inhibitors, which may lead to a new class of antiproliferative drugs.
authors.affiliation: Structural Biochemistry Group, The University of Edinburgh, Michael Swann Building, King's Buildings, EH9 3JR, Edinburgh, United Kingdom.
authors.forename: Su Ying
authors.initials: SY
authors.lastname: Wu
authors.forename: Iain
authors.initials: I
authors.lastname: McNae
authors.forename: George
authors.initials: G
authors.lastname: Kontopidis
authors.forename: Steven J
authors.initials: SJ
authors.lastname: McClue
authors.forename: Campbell
authors.initials: C
authors.lastname: McInnes
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Stewart
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.forename: Daniella I
authors.initials: DI
authors.lastname: Zheleva
authors.forename: Howard
authors.initials: H
authors.lastname: Marriage
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
authors.forename: Paul
authors.initials: P
authors.lastname: Taylor
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Walkinshaw
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D030562:Databases, Protein; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D046911:Macromolecular Substances; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D012984:Software
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D046911:Macromolecular Substances; D011725:Pyridines; D000255:Adenosine Triphosphate; D018844:Cyclin-Dependent Kinases