Structure-based inhibitor design

Based on the computational studies, synthetic pathways were developed to introduce an amino group at the C4 position on the Neu5Ac2en template, both in the natural equatorial configuration (16) [111,112] and in the axial (epi) configuration (17) [113]. 

In an in vitro fluorometric enzyme assay, 4-amino-4-deoxy-Neu5Ac2en 16 (A] 0.04 pM) [98,110] produced competitive inhibition of influenza virus sialidase 

---

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. 

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-... 

Purine Salvage Enzymes as Targets for Structure-Based Inhibitor Design... 

Structure-based inhibitor design of human hematopoietic prostaglandin D synthase 05Y739. 

Biochemical Reaction Mechanism of Scytalone Dehydratase and Structure-based Inhibitor Design... 

S.-H. Kim, PureAppl. Chem, 70, SS5 (1998). Structure-Based Inhibitor Design for CDK2, a Cell Cycle Controlling Protein. 

---