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

Muegge I, Martin YC, Hajduk PJ, Fesik SW
J Med Chem. 1999 42 (14): 2498-503

PMID: 10411471 · DOI:10.1021/jm990073x

A new knowledge-based scoring function (PMF-score), implemented into the DOCK4 program, was used to screen a database of 3247 small molecules for binding to the FK506 binding protein (FKBP). The computational ranking of these compounds was compared to the binding affinities measured by NMR. It was demonstrated that small, weakly binding molecules have, on average, higher computational 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 reliable ranking of small, weakly binding molecules offers new ways of designing building blocks in combinatorial libraries as well as SAR by NMR libraries with the increased chance of identifying suitable lead compounds for drug design.

MeSH Terms (10)

Binding Sites Immunophilins Immunosuppressive Agents Ligands Magnetic Resonance Spectroscopy Models, Molecular Molecular Weight Structure-Activity Relationship Tacrolimus Tacrolimus Binding Proteins

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