Insights from ab initio quantum chemical calculations into the preferred tautomeric forms and binding affinities to CDK2 of substituted pyrazolopyridines

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.