The transition from a pharmacophore-guided approach to a receptor-guided approach in the design of potent protein kinase C ligands

Citation
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
Citations number
54
Categorie Soggetti
Pharmacology & Toxicology
Journal title
PHARMACOLOGY & THERAPEUTICS
ISSN journal
01637258 → ACNP
Volume
82
Issue
2-3
Year of publication
1999
Pages
251 - 261
Database
ISI
SICI code
0163-7258(199905/06)82:2-3<251:TTFAPA>2.0.ZU;2-4
Abstract
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.