Comparative molecular field analysis (CoMFA) and QM/MM hybrid calculations were performed on 9H-purine derivatives as CDK2 inhibitors. CoMFA was carried out to describe the activities of 78 analogues. The models were applied to a training set including 64 compounds. The best CoMFA model included steric and electrostatic fields, had a good Q(2) value of 0.845, and adequately predicted the compounds contained in the test set. Furthermore, plots of the steric CoMFA field allowed conclusions to be drawn for the choice of suitable inhibitors. In addition, the dynamical behavior of compounds with 4-(aminosulfonyl)phenyl, 4-[(methylamino)sulfonyl]phenyl, 4-[(dimethylamino)sulfonyl]phenyl, and [3-methoxy-4-(aminosulfonyl)]phenyl groups at position 2 of the 9H-purine scaffold inside the CDK2 active site were analyzed by QM/MM calculations. The interactions of these compounds with residues Lys89, Asp86, and Ile10 were characterized.