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Based on the purine scaffold of ATP, derivatives of 6,9-diarylpurine-8-one were prepared and tested for their ability to inhibit p38 MAP kinase, a key enzyme in the cellular regulation of proinflammatory cytokines. The inhibitor design combines the purine system of the authentic cosubstrate ATP with various phenyl moieties to explore the selectivity for the two hydrophobic regions of the kinase's ATP-binding cleft. The present study indicates a new binding mode of our scaffold to p38 MAP kinase, which comprises the desired structural features of ATP and the N-phenyl-N-purin-6-yl ureas previously published by Wan et al. Combinations of Autodock and FlexX docking with different scoring functions were used to assess the postulated binding mode. The predictive power of different docking-scoring combinations was determined. The presented results may form a solid basis for further optimization cycles since our theoretical findings are consistent with our experimental binding data and supported by the literature. [ABSTRACT FROM AUTHOR]