Design of inhibitors

This experimental result offers a convincing rationalization for the slow deacylation of aztreonam in class C beta-lactamases. 

Molecular modeling indicated that in class C enzymes, the outward rotation around the C3-C4 bond would open the path for the water molecule to attack the ester. Such compounds are rapidly hydrolyzed by the class C enzymes [11]. Therefore, preventing this rotation in a 

5 Structure-Based Design of Potent Beta-Lactamase Irthibixors 

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DESIGN OF INHIBITORS FROM A SERIES OF STRUCTURALLY RELATED COMPOUNDS... 

Pande V, Ramos MJ (2005) NF-kappaB in human diseases current inhibitors and prospects for de novo structure-based design of inhibitors. Curr Med Chem 12 357-374... 

Cathepsin D. The design of inhibitors of the aspartyl protease cathepsin D started from a virtual library of peptide analogs that contained the typical hydroxyethylamine isoster for the cleavable peptide bond. As the availability of starting materials would have generated a library of about 1 billion compounds, virtual screening was applied to reduce this multitude of candidate structures to a reasonable number. The backbone of a peptide... 

A recent example of the success of the bisubstrate, transition state design approach comes from the work of Pope and coworkers (Pope et al., 1998a-c Brown et al., 2000) on the design of inhibitors of bacterial isoleucyl tRNA synthetase... 

In this example, structure-based design of inhibitors to the mutant enzyme may be undertaken using available X-ray structures and homology models. 

Secrist, S. Y. Babu, C. E. Bugg, W. C. Guida, and S. E. Ealick, Structure-based design of inhibitors of purine nucleoside phosphorylase, 3,9-arylmethyl derivatives of a 9-deazaguanine substituted on the methylene group, J. Med. Chem. 36 3771 (1993). 

Currently, this is a major application of protein crystallography in most of the major drug companies. One of the best examples of this approach is the design of inhibitors for HIV protease (Dash et al., 2003). In brief, once the 3-D structure of HIV protease was determined, the active site was identified and used to screen small molecule libraries for potential compounds that could bind to HIV protease. These compounds were then tested for their ability to inhibit the protease. Lead compounds were then used to iteratively improve the inhibitors, using crystallographic studies, computational modeling, and biochemical tests. 

Robert Chenevert is Professor of Organic Chemistry at Universite Laval, Quebec, Canada. He studied chemistry (B.Sc. and M.Sc.) at the Universite de Montreal. After receiving his Ph.D. in organic chemistry in 1975 at the Universite de Sherbrooke under the supervision of Professor Pierre Deslongchamps, he spent a postdoctoral year at Harvard (R. B. Woodward s group). His main research interest is the application of biocatalysts in asymmetric synthesis. He is also interested in the design of inhibitors of enzymes involved in the aminoacylation of tRNA (aminoacyl-tRNA synthetases and aminoacyl-tRNA amidotransferases). 

Current research from this laboratory (Figure 2) shows that the blocked hexapeptlde Ac-Ser-Pro-Phe-Arg-Ser-Gln-NH2 Inhibits kalllkreln In vitro (Kj = 6l pH) and demonstrates that the substrate analog approach Is applicable to the design of Inhibitors of kalllkreln. 

Many other approaches have been and are being developed for computeraided design of inhibitors. For example, pharmacophore analysis can identify the spatial arrangement of groups or atoms common to all active inhibitor molecules and then incorporate these elements into a single molecule [127,128]. 

Montgomery JA, Niwas S, Rose JD, Secrist JA 3d., Babu YS, Bugg CE, Erion MD, Guida WC, Ealick SE. Structure-based design of inhibitors of purine nucleoside phosphorylase. 1. 9-(arylmethyl) derivatives of 9-deazaguinine. J Med Chem 1993 36 55-69. 

While the interaction of the substrate (and the inhibitor) with the catalytic zinc is the most important interaction, the remainder of the substrate (inhibitor) also forms hydrogen bonds with residues from the top strand of the 3 sheet and the loop region posterior to the Met-tum. These interactions with the substrate in the binding pockets of the MMPs are the prime targets for engineering specific MMP inhibitors. An in-depth understanding of the differences of the properties of these pockets in the different MMPs and the interactions of specific residues within these pockets is essential for structure-based design of inhibitors. 

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