1w8c
From Proteopedia
CO-CRYSTAL STRUCTURE OF 6-CYCLOHEXYLMETHOXY-8-ISOPROPYL-9H-PURIN-2- YLAMINE AND MONOMERIC CDK2
Structural highlights
Evolutionary ConservationCheck, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedEvaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O6-cyclohexylmethylguanine derivatives, revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a 'reverse' binding mode where the purine backbone has flipped 180 degrees . This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these 'reverse' binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited sub-micromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography. 8-Substituted O6-Cyclohexylmethylguanine CDK2 Inhibitors; Using Structure-Based Inhibitor Design to Optimise an Alternative Binding Mode.,Carbain B, Paterson DJ, Anscombe E, Campbell-Dexter A, Cano C, Echalier A, Endicott J, Golding BT, Haggerty K, Hardcastle IR, Jewsbury PJ, Newell DR, Noble M, Roche C, Wang LZ, Griffin RJ J Med Chem. 2013 Dec 4. PMID:24304238[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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