Inhibitors rational design

Flow chart showing the design of novel orally active HIV-1 protease inhibitor. (Figure adapted from Lam P K ]adhav, C E Eyermann, C N Hodge, Y Ru, L T Bacheler, ] L Meek, M ] Otto, M M Rayner, Y N V /ong, ang, P C Weber, D A Jackson, T R Sharpe and S Erickson-Viitanen 1994. Rational Design of Potent, able. Nonpeptide Cyclic Ureas as HIV Protease Inhibitors. Science 263 380-384.)... 

Penam Sulfone B-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of p-lactamase inhibitors based on the readily accessible penicillin nucleus. An early success was penicillanic acid sulfone, (2(5)-cis)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-a2abicyclo [3.2.0]heptane-2-carboxylic acid [68373-14-8] (sulbactam) (25, R = = H, R" = R" = CH ), CgH NO S. The synthesis (118), microbiology (119—121),... 

A number of rationally designed MMP inhibitors have shown some promise in the treatment of pathologies, which MMPs are suspected to be involved in. However, most of these, such as Marimastat (BB-2516), a broad spectrum MMP inhibitor, or trocade (Ro 32-3555), an MMP-1 selective inhibitor, have performed poorly in clinical trials. The failure of Marimastat was partially responsible for the folding of British Biotech, which developed it. The failure of... 

Nelfinavir is a nonpeptidic, rationally designed HIV protease inhibitor. Nelfinavir has demonstrated efficacy in both monotherapy and in combination with the reverse transcriptase inhibitors stavudine (d4T) or zivudine + 3TC. The major side effect is mild to moderate diarrhea. 

Von Itzstein M, Wu WY, Kok GB, Pegg MS, Oyason JC, Jin B. et al. Rational design of potent siaidase-based inhibitors of influenza-virus replication. Nature... 

Lam PYS, Jadhav PK, Eyermann CJ, Hodge CN, Ru Y, Bacheler LT, Meek JL, Otto MJ, Rayner MM, Wong YN, Chang CH, Weber PC, Jackson DA, Sharpe TR, Erickson-Viitanen S. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science 1994 263 380-4. 

Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci USA 2004 101 7618-23. 

Shaw JP, Johnson Z, Borlat F, et al. The X-ray structure of RANTES heparin-derived disaccharides allows the rational design of chemokine inhibitors. Structure (Cambridge) 2004 12 2081-93. 

With the advance of X-ray crystalography and the ability to determine the three dimensional structure of the kinase with the bound inhibitor, drug design has become more precise and rational. The three dimensional structures of a two tyrosine kinases complexed with a kinase inhibitor have already been solved ... 

Concept A new approach to the rational design of enzyme inhibitors has emerged in the last ten to fifteen years that incorporates a substrate (or transition state) analog "core" molecule with additional binding determinants spanning beyond the immediate... 

A J. Broom, Rational Design of Enzyme Inhibitors Multisubstrate Analogue Inhibitors ,/ Med Chem. 1989, 32 2-7. 

Peptidyl-dipeptidase A (angiotensin-I converting enzyme, ACE, EC 3.4.15.1) plays a pivotal role in the control of blood pressure [80]. It has been established that its active site contains an essential Zn-atom that functions like that of carboxypeptidase A [2], ACE is inhibited by peptides having a proline or aromatic amino acid at the C-terminal position. These observations as well as the similarities with the active site of carboxypeptidase A have allowed a rational design of effective inhibitors of ACE (e.g., captopril (3.4) and enalapril (3.5)) used in the treatment of hypertension [81]. 

Often, crystallography is used as a tool for improving inhibitors that already exist. It can be quite difficult to rationally design an inhibitor from scratch, but improvements to known inhibitors can be easily and rapidly modeled. Potential improved inhibitors can then be designed and tested. This can be an iterative process with subsequent rounds of inhibitors designed from each subsequent improvement. 

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