title: Insights from ab initio quantum chemical calculations into the preferred tautomeric forms and binding affinities to CDK2 of substituted pyrazolopyridines.
abstract: Ab initio calculations were employed to compute pKa values and tautomer properties of a series of substituted pyrazolopyridines. The results show that the neutral 1H tautomer predominates, but upon protonation this proton migrates to give the preferred charged [2H,7H] tautomer. The basicity of the pyrazolopyridines is correlated with the electron donating capability of the 4-substituent. Ab initio free energy calculations were also used to identify determinants of binding affinity for some recently published pyrazolopyridine inhibitors of CDK2. Hydrogen-bonding affinity may be one important component of binding strength.
authors.affiliation: Department of Structural Chemistry, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. jose.duca@spcorp.com
authors.forename: José S
authors.initials: JS
authors.lastname: Duca
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Madison
mesh_terms: D001665:Binding Sites; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007536:Isomerism; D007700:Kinetics; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2