Structural analysis of thrombin complexed with potent inhibitors incorporating a phenyl group as a peptide mimetic and aminopyridines as guanidine substitutes.
The structure of the noncovalent complex of human alpha-thrombin with a nonpeptide inhibitor containing a central phenyl scaffold, N-[2-[5-methyl-3-(2-chlorophenylsulfonyloxy)phenoxy]ethyl]-N- methyl-4 -aminopyridine (1), has been determined to 2.20 A resolution. In addition, the thrombin-bound structures of two distinct amino acid-based inhibitors (3 and 4) containing different aminopyridine-derived guanidine mimetics have been determined. Each compound occupies the same region of the active site and projects an aminopyridine, a central hydrophobic group, and an aryl group, into the S1, S2, and aryl subsites on thrombin. Nonpeptide 1 forms only one direct intermolecular hydrogen bond to the thrombin active site and forms no hydrogen bonds to ordered molecules of solvent. Close contacts are observed between main-chain carbonyl groups on thrombin and the edges of the central phenyl and aminopyridine rings and the sulfonyl group of 1 such that atoms carrying opposite partial charges are juxtaposed. Aminopyridine groups in 3 and 4 also form close contacts with the edges of carbonyl groups on thrombin and are flexibly accommodated in the S1 subsite. Superposition of the bound conformations of 1 and D-Phe-Pro-amidobutylguanidine (2) revealed that the central phenyl scaffold of 1 substitutes for the peptide main chain of 2.
Bone
R
R
3-Dimensional Pharmaceuticals Inc., Eagleview Corporate Center, 665 Stockton Drive, Suite 104, Exton, Pennsylvania 19341, USA.
Lu
T
T
Illig
C R
CR
Soll
R M
RM
Spurlino
J C
JC
D000631:Aminopyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006146:Guanidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D011487:Protein Conformation; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
D000631:Aminopyridines; D004151:Dipeptides; D004791:Enzyme Inhibitors; D006146:Guanidines; C112579:N-(2-(5-methyl-3-(2-chlorophenylsulfonyloxy)phenoxy)ethyl)-N-methyl-4-aminopyridine; C112581:phenylalanyl-prolyl-amidobutylguanidine; D013917:Thrombin