Structure-based inhibitor

CS Ring, E Sun, JH McKerrow, GK Lee, PI Rosenthal, ID Kuntz, EE Cohen. Structure-based inhibitor design by using protein models for the development of antiparasitic agents. Proc Natl Acad Sci USA 90 3583-3587, 1993. 

Wlodawer A, Erickson JW (1993) Structure-based inhibitors of HIV-1 protease. Annu Rev Biochem 62 543-585... 

Soelaiman S, Wei BQ, Bergson P, Lee YS, Shen Y, Mrksich M, Shoichet BK, Tang WJ. Structure-based inhibitor discovery against adenylyl cyclase toxins from pathogenic bacteria that cause anthrax and whooping cough. J Biol Chem 2003 278 25990-7. 

S. Singh, M. J. Jedrzejas, G. M. Air, M. Luo, W. G. Laver, and W. J. Brouillette, Structure-based inhibitors of influenza virus sialidase A benzoic acid lead with novel interaction, J. Med. Chem., 38 (1995) 3217-3225. 

Lin TW, Melgar MM, Kurth D et al (2006) Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltrans-ferase domain of Mycobacterium tuberculosis. Proc Natl Acad Sci USA 103 3072-3077... 

Proc. Natl. Acad. Sci. U.S.A. 90, 3538 (1993). Structure-Based Inhibitor Design by Using Protein Models for the Development of Antiparasitic Agents. 

Structure-based inhibitor design relies on the known inhibitor-receptor 3D structure. This could be obtained either by previously mentioned experimental methods or by docking the lead into the active site of the free receptor. On the basis of this structure, the lead compound is modified in a way that adds groups to enhance binding to the receptor. 

Some other hydrolytic enzymes, in addition to proteases, that are important drug targets include protein phophatases, phosphodiesterases, nucleoside hydrolases, acetylhydolases, glycosylases, and phospholipases. Structure-based inhibitor design is currently being applied to a number of these enzymes. The last three mentioned have been successfully tar-... 

In the recent studies, the enzyme shows that the overall polypeptide fold of chymotrypsin-like serine protease possesses essential SI specificity determinants characteristic of elastase using the multiple isomorphous replacement (MIR) method and refined to 2.3 A resolution Fig. (5). Structure-based inhibitor modeling demonstrated that EFEa s SI specificity pocket is preferable for elastase-specific small hydrophobic PI residues, while its accommodation of long and/or bulky PI residues is also feasible if enhanced binding of the substrate and induced fit of the SI pocket are achieved [Fig. (6) shows the active sites of serine protease]. EFEa is thereby endowed with relatively broad substrate specificity, including the dual fibrinolysis. This structure is the first report of an earthworm fibrinolytic enzyme component, a serine protease originated from annelid worm [17]. 

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