Enzyme inhibitors applications

Chem., 39, 705 (1996). An Approach to Rapid Estimation of Relative Binding Affinities of Enzyme Inhibitors Application to Peptidomimetic Inhibitors of the Human Immunodeficiency Virus Type 1 Protease. 

Viswanadhan YN, Reddy MR, Wlodawer A, Varney MD, Weinstein JN. An approach to rapid estimation of relative binding affinities of enzyme inhibitors application to pep-tidomimetic inhibitors of the human immunodeficiency virus type 1 protease. J Med Chem 1996 39 705-712. 

V. N. Viswanadhan, M. R. Reddy, A. Wlodawer, M. D. Varney, and J. N. Einstein,/. Med. Chem., 39, 705 (1996). An Approach to Rapid Estimation of Relative Binding Affinities of Enzyme Inhibitors Application to Peptidomimetic Inhibitors of the Human Immunodeficiency Type 1 Protease. 

Application of the CCM to small sets (n < 6) of enzyme inhibitors revealed correlations between the inhibitory activity and the chirality measure of the inhibitors, calculated by Eq. (26) for the entire structure or for the substructure that interacts with the enzyme (pharmacophore) [41], This was done for arylammonium inhibitors of trypsin, Di-dopamine receptor inhibitors, and organophosphate inhibitors of trypsin, acetylcholine esterase, and butyrylcholine esterase. Because the CCM values are equal for opposite enantiomers, the method had to be applied separately to the two families of enantiomers (R- and S-enantiomers). 

A special application of heteroaromatic acylation via a modified Dakin-West reaction leads to a-fluoro ketone derivatives [50] (equation 30) Such fluoro ketones have been successfully used as enzyme inhibitors in modern bioorganic chemistry [5, 6]... 

Cavalli A, Greco G, Novellino E, Recanatini M. Linking CoMFA and protein homology models of enzyme-inhibitor interactions an application to nonsteroidal aromatase inhibitors. Bioorg Med Chem 2000 8 2771-80. 

DeFrank 11 (1991) Organophosphorus cholinesterase inhibitors detoxification by microbial enzymes. In Applications of Enzyme Biotechnology (Ed IW Kelly and TO Baldwin), pp. 165-180. Plenum Press, New York. 

The final part is devoted to a survey of molecular properties of special interest to the medicinal chemist. The Theory of Atoms in Molecules by R. F.W. Bader et al., presented in Chapter 7, enables the quantitative use of chemical concepts, for example those of the functional group in organic chemistry or molecular similarity in medicinal chemistry, for prediction and understanding of chemical processes. This contribution also discusses possible applications of the theory to QSAR. Another important property that can be derived by use of QC calculations is the molecular electrostatic potential. J.S. Murray and P. Politzer describe the use of this property for description of noncovalent interactions between ligand and receptor, and the design of new compounds with specific features (Chapter 8). In Chapter 9, H.D. and M. Holtje describe the use of QC methods to parameterize force-field parameters, and applications to a pharmacophore search of enzyme inhibitors. The authors also show the use of QC methods for investigation of charge-transfer complexes. 

All these advances have resulted not only in increases in resolution but have also alleviated the detection problems to a considerable extent. As a result, the last decade has seen a dramatic growth in 15N- and 170-NMR spectroscopy as a versatile method for studying molecular structure, both in isotropic (liquid) and anisotropic (solid) phases. Studies at a natural abundance level of the nucleides are now commonplace. The scope of chemical applications extends from inorganic, organometallic and organic chemistry to biochemistry and molecular biology, and includes the study of reactive intermediates, biopolymers and enzyme-inhibitor complexes. 

The application of multiple reaction parameters executed in a parallel array format has been used to expedite the identification of optimal conditions for the synthesis of a collection of almost 600 new interleukin-1/ converting enzyme inhibitors [89]. The reaction in question was the problematic conversion of a / -tert-butyl aspartic acid bromoethylketone to the corresponding acyloxyketone (Scheme 2.63). The study en-... 

Other interesting applications of the ophcally active cyanohydrins obtained by (R)-oxynitrilase-catalyzed processes are the produchon of the blockbuster clopido-grel (Scheme 10.23) [52], and the angiotensin-converhng enzyme inhibitors enala-pril and lisinopril (Scheme 10.24) [53, 54]. 

The earliest applications of bioaffinity chromatography involved its use in enzyme purification (see Figure 13.7) [7]. Enzyme purification has continued to be a major application of this technique [57]. Some ligands that are employed for this purpose are enzyme inhibitors, coenzymes, substrates, and cofactors. Examples include methods that use nucleotide mono-, di-, and triphosphates for the... 

Saccharidic Difluorophosphonates Difluoromethylene phospho-nates have been the focus of numerous works. Indeed, these compounds are able to mimic the phosphate bond in the synthesis of enzyme inhibitors. This interest is obvious for the furanose series in this case, they are non scissible analogues of 5-phosphate nucleosides (cf. Chapter 7). Difluoromethylene phosphonates can be prepared via a radical path starting from compounds that have the difluoromethylene moiety in the pseudo-anomeric position. Nevertheless, methods based on metal derivatives of difluorophosphonates are generally easier and broadly applicable. 

Enzyme-sensitive supramolecular polymers also hold promise in analytical applications such as the screening of enzyme inhibitors. A simple visual assay based on the hydrogelation of small molecules has been developed for screening the activities of inhibitors of enzymes like acid phosphatase. A number of inhibitors for... 

The biosynthesis of the IL-12 cytokine is dependent upon various enzymes, including phosphodiesterase 4 (PDE4). Thus, PDE4 enzyme inhibitors act as functional IL-12 antagonists, and may have clinical application in the treatment of rheumatoid arthritis. 

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