D. Green et al., X-ray crystallographic analyses of human alpha-thrombin complexed to peptidy aminophosphonates: Evidence of a binding mechanism, PHOSPHOR SU, 146, 1999, pp. 545-548
Citations number
26
Categorie Soggetti
Inorganic & Nuclear Chemistry
Journal title
PHOSPHORUS SULFUR AND SILICON AND THE RELATED ELEMENTS
We sought to study O,O-Diphenyl dipeptidylaminophosphonates and their inter
action with the coagulation protease, human a-thrombin. The 'fibrinogen-lik
e' recognition sequence D-Phe-Pro-Arg, is a template of high affinity for t
hrombin. This was modified by replacing the 'P1' Arg by a neutral side chai
n, and the unnatural amino acid diphenylalanine was used in place of the 'P
3' Phe. The tripeptides of general formula D-Dpa-Pro-NHCHRP(OPh)(2) are hig
hly selective for thrombin amongst other serine proteases; and, more import
antly fbr the design of an efficacious anti-thrombotic agent, show particul
arly low activity toward other coagulation serine proteases of the cascade.
However the kinetics of thrombin inhibition were seen to be dependent on t
he compounds' structure. To explain this we have studied compounds (1), whe
re R is pentyl and compound (2) where ii is (3-methoxy)propyl, for which th
e kinetics of inhibition were analysed as competitive (2 mu M) and slow, ti
ght-binding (final K-i 20nM) respectively. Analysis of the X-Ray crystal st
ructure of these compounds complexed to human a-thrombin, unusually shows n
o covalent bond formed between the phosphorus nucleus and the serine 195 in
the catalytic site of the enzyme. These observations are at variance to th
e proposed mechanism of action of other phosphorus based serine protease in
hibitors.