| Abstract
| - Precise thermodynamic integration free energy simulations have been applied to a congenericseries of 16 inhibitors to the p38 MAP kinase protein for which the experimental binding data(IC50) is known. The relative free energy of binding for each compound has been determined.For comparison, the same series of compounds have also scored using the best rapid scoringfunctions used in database screening. From the results of these calculations, we find (1) thatprecise free energy simulations allow predictions that are reliable and in good agreement withexperiment; (2) that predictions of lower reliability, but still in good qualitative agreementwith experiment, can be obtained using the OWFEG free energy grid method, at a much lowercomputational cost; (3) and that other methods, not based on free energy simulations yieldresults in much poorer agreement with experiment. A new predictive index, which measuresthe reliability of a prediction method in the context of normal use, is defined and calculatedfor each scoring method. Predictive indices of 0.84, 0.56, 0.04, −0.05, and 0.25 are calculatedfor thermodynamic integration, OWFEG, ChemScore, PLPScore, and Dock Energy Score,respectively, where +1.0 is perfect correct prediction, −1.0 is perfect incorrect prediction, and0.0 is random.
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