Inhibitors design

Jedrzejas, M. J., Singh, S. Brouillette, W. J. Air, G. M. Luo, M. A. 1995. Strategy for theoretical binding constant, Ki calculation for neuraminidase aromatic inhibitors, designed on the basis of the active site structure of influenza virus neuraminidase. Proteins Struct. Funct. Genet. 23 (1995) 264-277... 

Computer-aided inhibitor design is a relatively new and powerful approach for the development of novel, potentially potent, nonsubstrate-analogue enzyme inhibitors. Computer-aided methods and biological screening can each lead to new classes of novel inhibitors. However, computer-aided design methods can focus the search for inhibitors, thereby circumventing much of the time-consuming synthetic and natural product purification procedures for those compounds they find unlikely to function as inhibitors. 

Fig. 8. Thymidylate synthase inhibitors designed to fit into the A/, AJ -methylenetetrahydrofolate binding site. The best inhibitors from each class are the classical antifolate TS inhibitor (31), the naphthostyril-based lead compound (32), and the tetrahydroquinoline-based lead compound (33), iC values (in nAI)...

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. 

Fig. 5.14. Substrate inhibition plots for batch system with top left comer showing the concentration of substrate inhibitor designated by [5 ] (Left Hanes-woolf Right Curve fit).

Olejniczak ET, Hajduk PJ, Marcotte PA et al (1997) Stromelysin inhibitors designed from weakly bound fragments effects of linking and cooperativity. J Am Chem Soc 119 5828-5832... 

Inhibitor Design Using Five-Membered Ring Templates... 

Fig. 1.13 Adenosine kinase inhibitor designed using fragment optimization approach.

Frederick, R. Robert, S. Charlier, C. de Ruyck, J. Wouters, J. Masereel, B. Pochet, L. Mechanism-based thrombin inhibitors design, synthesis, and molecular docking of a new selective 2-OXO-2/7- l-benzopyxan derivative. J. Med. Chem. 2007, 50, 3645-3650. 

It is worth noting here that inhibitors that interact with enzyme active site functionalities in ways that mimic the structure of covalent intermediates of catalysis can bind with very high affinity. This was seen in Chapter 1 with the example of statine-and hydroxyethylene-based inhibitors of aspartic proteases other examples of this inhibitor design strategy will be seen in subsequent chapters of this text. 

Many examples exist of potent enzyme inhibitors that function as transition state mimics (see Chapter 7 Schramm, 1998, and Wolfenden, 1999, for some examples). An understanding of the transition state structure is thus of great valuable for inhibitor design. As described in Chapter 1, the transition state is not the only inter-... 

Three-dimensional X-ray crystal structures of the SET domains of >10 PMTs and the catalytic domain of DOT1L have been reported to date [25-27]. These structures, either in the apo-state or when bound to the cofactor product S-adenosyl-L-homocysteine (SAH), a histone peptide, or an inhibitor, yield key structural insights into enzyme/substrate/cofactor/inhibitor interactions and inform approaches to further inhibitor design. 

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