Active site inhibitors

X-Ray crystal structures of four 6-strand-templated active site inhibitors of thrombin, including compounds MOL-126 and MOL-174 (Section 12.10.15.2 ), have been determined and refined at about 2.1 A resolution to crystallographic R-values between 0.148 and 0.164 <1999JME1376>. 

In vivo the corresponding parameter to a K is A iiv, a parameter that is determined directly from in vivo experiments. Theoretically, K and K should be equal, but for the reasons outlined above they may not be. K is a direct measure of the molecular interaction of the drug with the enzyme. A iiv on the other hand is a measure of the actual in vivo effectiveness of the inhibitor. That is /(" iv, unlike Kj, automatically incorporates into its value the effects of factors such as differences in active site inhibitor concentration,... 

Tsuda Y, Cygler M, Gibbs BF, Pedyczak A, Fethiere J, Yue SY, Konishi Y. Design of potent bivalent thrombin inhibitors based on hirudin sequence incorporation of nonsubstrate-type active site inhibitors. Biochemistry 1994 33 14443-14451. 

Lockene, A., Skottova, N., Olivecrona, G. Interactions of Lipoprotein Lipase with the Active-Site Inhibitor Tetrahydrolipstatin (Orlistat). Eur. J. Biochem. 1994, 222, 395 103. 

J., Luque, F.J., Gago, F. Modulation of Binding Strength in Several Classes of Active Site Inhibitors of Acetylcholinesterase Studied by Comparative Binding Energy Analysis. /. Med. Chem. 2004, 47, 4471-4482. 

Mehta JL, Chen L, Nichols VVW, et al. Melagatran, an oral active-site inhibitor of thrombin, prevents or delays formation of electrically induced occlusive thrombus in the canine coronary artery. J Cardiovasc Pharmacol 1998 3 1 345-351. 

Captopril (14) is a competitive inhibitor of ACE, with K, = 1.7 x 10-9 M. Its inhibitory activity does not increase with time and is reversible on dilution. These properties and the analogue studies referenced above support its designation as an active site inhibitor not functioning by... 

Schumacher WA, Heran CL, Steinbacher TE (1996a) Low-molecular-weight heparin (Fragmin) and thrombin active-site inhibitor (argatroban) compared in experimental arterial and venous thrombosis and bleeding time. J Card Pharmacol 28 19-25... 

The third criterion of the inhibition of fertilization by active site inhibitors was observed both In vitro (63) and in vivo (64) fertilization. However, this inhibition was never total, and once the sperm had tightly bound the ZP, trypsin active site inhibitors did not prevent further penetration or hydrolysis of the ZP (65). Therefore, while acrosin does not strictly follow all of the criteria for a ZP lysin, it does cause limited hydrolysis of the ZP and it is in the correct place to act in penetration of the ZP. 

Figure 3 Competitive, active site inhibitors of proteases. These inhibitors bind in the active site, but not in a substrate-like manner. Peptide extensions bind in specificity subsites, and sometimes interact with the catalytic residues (rectangle), but not in a catalytically competent manner.

Nilsson T, Sjoling-Ericksson A, Deinum J. The mechanism of binding of low-molecular-weight active site inhibitors to human alpha-thrombin. J. Enzyme Inhib. 1998 13 11-29. 

Das J, Kimball SD. Thrombin active site inhibitors. Bioorg Med Chem 1995 3 999-1007. 

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