Structural basis for the activity of pp60(c-src) protein tyrosine kinase inhibitors.
Conformational searches on three closely related pp60(c-src) protein tyrosine kinase inhibitors of varying potencies were performed to determine a structural basis for their activity. The first was a linear peptide (PDNEYAFFQf), the second its 10-membered cyclic analogue, and the third a cyclic analogue with a para carboxyphenylalanine in place of one the F residues. A common backbone conformation with an antiparallel beta-sheet-like geometry capped by similar beta-turns was found for all three peptides, which may be a binding conformation and gives a candidate pharmacophore for further testing. The interaction between some polar side chains and between some of the aromatic rings may be important for maintaining the correct conformation. The differences in potencies of these inhibitors may be attributed to certain thermodynamic and chemical reasons.
Prabhu
N V
NV
Department of Chemistry, University of Houston, Houston, TX 77204-5641, USA.
Siddiqui
S A
SA
McMurray
J S
JS
Pettitt
B M
BM
D000595:Amino Acid Sequence; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012984:Software; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010456:Peptides, Cyclic; D016392:Proto-Oncogene Proteins pp60(c-src)