Ve. Marquez et al., The transition from a pharmacophore-guided approach to a receptor-guided approach in the design of potent protein kinase C ligands, PHARM THERA, 82(2-3), 1999, pp. 251-261
The pharmacophore-guided approach used in the first phase of the design of
novel protein kinase C (PKC) ligands was based on the study of the geometry
of bioequivalent pharmacophores present in diacylglycerol (DAG) and in the
more potent phorbol ester tumor promoters. A number of potent DAG lactones
were generated by this approach, in which the glycerol backbone was constr
ained into various heterocyclic rings to reduce the entropic penalty associ
ated with DAG binding. Based on the information provided by X-ray and NMR s
tructures of the cysteine-rich, CI phorbol ester/DAG binding domain, the DA
G lactones were further modified to optimize their interaction with a group
of highly conserved hydrophobic amino acids along the rim of the C1 domain
. This receptor-guided approach culminated with the synthesis of a series o
f "super DAG" molecules that can bind to PKC with low nanomolar affinities.
These compounds provide insight into the basis for PKC ligand specificity.
Moreover, some of the compounds reviewed herein show potential utility as
antitumor agents. (C) 1999 Elsevier Science Inc. All rights reserved.