Journal of Medicinal Chemistry · 1994 · 56 citations · 0 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryPharmacophore ModelingComputational Drug DiscoveryLigand BindingMolecular DockingPharmacophore ScreeningPharmacophore-based Lead DiscoveryReceptor-ligand Interactions3D Molecular Modeling3D Pharmacophore SearchBinding Affinity AssessmentComputational Molecular ModelingPharmacophore Model ConstructionPharmacophore-based Database SearchingPost-synthetic ModificationProtein-ligand Interaction Pharmacophore Models
A computer protein kinase C (PK-C) pharmacophore search on 206,876 nonproprietary 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 marginal, binding affinities. Molecular modeling studies showed that in addition 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 confirmed by synthetic modification of two inactive compounds, producing two active derivatives. These newly discovered, structurally diverse lead compounds are being used as the basis for further synthetic modifications aimed at more potent PK-C ligands that will compete with the phorbol esters.