Protein Kinase C. Modeling of the Binding Site and Prediction of Bindings
Shaomeng Wang, George W. A. Milne*, Marc C. Nicklaus, Victor E. Marquez, Jeewoo Lee, and Peter Blumberg
Laboratory of Medicinal Chemistry, DCT, and Laboratory of Cellular Carcinogenesis and Tumor Promotion, DCE, National Cancer Institute, NIH, Bethedsa, Maryland 20892.
Received November 23, 1984
A detailed examination of the mode of binding of phorbol esters to protein kinase C led to a model of the phorbol binding site in the enzyme. The efficacy with which various synthetic diacylglycerol analogs and ribonolactones are able to bind to this site was determined by means of semiempirical quantum mechanical calculations using PM3, and an estimate of the binding energy was made in each case. Sixteen synthetic analogs of 1,2-diacylglycerol and two natural products were studied and their calculated energies of binding to this model were correlated with the measured K¡ values. The binding energies calculated for this receptor model, together with solubility and entropy considerations, allow predicition through regressive fit of free energies of binding which correlate very well with the measured binding constants.