THE DISCOVERY OF NOVEL, STRUCTURALLY DIVERSE PROTEIN-KINASE-C AGONISTS THROUGH COMPUTER 3D-DATABASE PHARMACOPHORE SEARCH - MOLECULAR MODELING STUDIES

A computer protein kinase C (PK-C) pharmacophore search on 206 876 non proprietary structures in the NCI 3D-database led to the discovery of five compounds which were found to possess PK-C binding affinities in the low micromolar range and six others having detectable, but margina l, binding affinities. Molecular modeling studies showed that in addit ion to, the presence of the defined pharmacophore, hydrophobicity and conformational energy are the two other important factors determining the PK-C binding affinity of a compound. The modeling results were con firmed by synthetic modification of two inactive compounds, producing two active derivatives. These newly discovered, structurally diverse l ead compounds are being used as the basis for further synthetic modifi cations aimed at more potent PK-C ligands that will compete with the p horbol esters.