Evaluation of PMF scoring in docking weak ligands to the FK506 binding protein

A new knowledge-based scoring function (PMF-score), implemented into the DO CK4 program, was used to screen a database of 3247 small molecules for bind ing to the FK506 binding protein (FKBP). The computational ranking of these compounds was compared to the binding affinities measured by NMR. It was d emonstrated that small, weakly binding molecules have, on average, higher c omputational scores than nonbinders and are enriched in the upper ranks of the computational scoring lists. In addition, the results obtained with the PMF scoring function were superior (by 30-120% larger enrichment factors) to those obtained with the standard force field score of DOCK4. The reliabl e ranking of small, weakly binding molecules offers new ways of designing b uilding blocks in combinatorial libraries as well as SAR by NMR libraries w ith the increased chance of identifying suitable lead compounds for-drug de sign.