title: Structure-based approaches to improve selectivity: CDK2-GSK3beta binding site analysis.
abstract: An evaluation and comparison of two different approaches, GRID/CPCA and GRIND/CPCA (CPCA = consensus principal component analysis; GRIND = GRid-INdependent Descriptors), suitable for visualizing the structural differences between related proteins is presented. Ten crystal structures of CDK2/cyclin A and GSK3beta solved in-house with different inhibitors were compared with the aim of highlighting regions that could be potential sites for gaining selectivity for CDK2 versus GSK3beta. The analyses pointed out remarkable differences in the backs of the CDK2-GSK3beta ATP binding pockets that guided the optimization toward a selective benzodipyrazole CDK2 inhibitor. The gain in selectivity can be associated with the two main differences in the ATP pocket between the enzymes. Phe80 of CDK2, the so-called gatekeeper residue often exploited for the design of kinase selective ligands, is replaced by a leucine in GSK3beta, and Ala144 is replaced by a cysteine. As a consequence of these mutations, CDK2 has a less elongated and less flat buried region at the back of the ATP pocket.
authors.affiliation: Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy. anna.vulpetti@nervianoms.com
authors.forename: Anna
authors.initials: A
authors.lastname: Vulpetti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Crivori
authors.forename: Alexander
authors.initials: A
authors.lastname: Cameron
authors.forename: Jay
authors.initials: J
authors.lastname: Bertrand
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Brasca
authors.forename: Roberto
authors.initials: R
authors.lastname: D'Alessio
authors.forename: Paolo
authors.initials: P
authors.lastname: Pevarello
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D003460:Crystallization; D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000737:chemistry / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008958:Models, Molecular; D025341:Principal Component Analysis; D011485:Protein Binding; D011487:Protein Conformation; D012680:Sensitivity and Specificity; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D019925:Cyclin A; D000255:Adenosine Triphosphate; D000071679:Glycogen Synthase Kinase 3 beta; D051357:Cyclin-Dependent Kinase 2; D038362:Glycogen Synthase Kinase 3