Phosphatase inhibitor design

Ye, B., and Burke, T.R., Jr., Synthesis of a difluorophosphonomethyl-containing phosphatase inhibitor designed from the X-ray structure of a PTPlB-bound hgand. Tetrahedron, 52, 9963, 1996. 

Umezawa K, Kawakami M, Watanabe T. Molecular design and biological activities of protein-tyrosine phosphatase inhibitors. Pharmacol Ther 2003 99 15-24. 

True enough, treatment of PAP with FMPP resulted in a time-dependent inactivation of the enzyme. Competitive inhibitors of PAP protected against inactivation. The authors suggest that FMPP represents a useful basic structure which can be incorporated into the design of more specific phosphatase inhibitors for example, the modified tyrosine 77 could be incorporated into a particular peptide to give a suicide substrate that is selective for a protein phosphatase which preferentially hydrolyses that peptide. 

Vazquez, J., Tautz, L., Ryan, J. J., Vuori, K., Mustelin, T., and Pellecchia, M. (2007). Development of molecular probes for second-site screening and design of protein tyrosine phosphatase inhibitors. Journal of Medicinal Chemistry 50, 2137-2143. 

Ortlund E, LaCount MW, Lebioda L (2003) Crystal structures of human prostatic acid phosphatase in complex with a phosphate ion and alpha-benzylaminobenzylphosphonic acid update the mechanistic picture and offer new insights into inhibitor design. Biochemistry 42 383-389... 

Puius YA, Zhao Y, Sullivan M et al (1997) Identification of a second aryl phosphate-binding site in protein-tyrosine phosphatase IB a paradigm for inhibitor design. Proc Natl Acad Sci U S A 94 13420-13425... 

The pyrrole nucleus is commonly found in biologically active lead compounds and designed analogs, and two out of many recently published examples will be mentioned here. The pyrrole core structures of roseophilin and prodigiosin have been studied as protein tyrosine phosphatase inhibitors <04CBC1575>. A new class of 2-vinylpyrroles, 6-pyrrolyl-2,4-dioxo-5-hexenoic acids, were found to be active HIV-1 integrase inhibitors <04BMCL1745>. 

Strategies for Designing Specific Protein Tyrosine Phosphatase inhibitors and Their intraceiiuiar Activation... 

Related to the incorporation of known pharmacophores into libraries, are those libraries utilizing biologically active natural products as design anchors. Library 2.6, based on the protein phosphatase inhibitor, calyculin-A, and library 4.10, derived from the antibacterial, neomycin B, illustrate this strategy. 

The formal insertion of chlorocarbene into organoboranes obeys the same rules. It is the cornerstone of the regio- and stereoselective chain elongation designed by Don Matteson. His asymmetric synthesis of stegobinone (37, Scheme 1-29) and the related partial synthesis of the phosphatase inhibitor tautomycin illustrate impressively the potential of this approach. 

Examples of such systems include the reactions of kinases, phosphatases, hydroxylases, acetylases, ubiquitin transferases, and many other enzyme classes that represent attractive targets for drug discovery. There are several mechanisms by which an enzyme can catalyze these types of reactions, and the details of the mechanism are important in determining the best approach to designing activity assays for the enzyme and for proper evaluation of inhibitors that are identified through those activity assays. 

AGIRE computer program for, 249, 79-81, 225-226 comparison to analysis based on rates, 249, 61-63 complex reactions, 249, 75-78 experimental design, 249, 84-85 inhibitor effects, 249, 71-75 potato acid phosphatase product inhibition, 249, 73-74 preliminary fitting, 249, 82-84 prephenate dehydratase product inhibition, 249, 72-73 product inhibition effects, 249, 72-73 prostate acid phosphatase phenyl phosphate hydrolysis, 249, 70 reactions with two substrates, 249, 75-77 reversible reactions, 249, 77-78 with simple Michaelian enzyme, 249, 63-71 [fitting equations, 249, 63] with slow-binding inhibitors, 249, 88 with unstable enzymes, for kinetic characterization, 249, 85-89. 

Although detailed structural as well as mechanistic knowledge of an enzyme is desirable, it is by no means necessary in order to design a suicide substrate. This has been shown by Myers and Widlanski (1993) who have designed a simple inhibitor of human prostatic acid phosphatase (PAP), an enzyme that is believed to be involved in the regulation of androgen receptor activity in prostate cells. Since the enzyme shows a preference for hydrolysis of aryl phosphates, the 4-(fluoromethyl)-phenyl phosphate (FMPP) was prepared as a substrate that would, on hydrolysis by the... 

A small focused hbrary, shown in Fig. 5.5, which was reported by Wipf and co-workers (8, 9), was designed to exploit the information provided by natural inhibitors of serine/threonine protein phosphatases (why) and to gain additional... 

SAR-by-NMR represents a very intuitive way of rational, fragment-based drug design. Two or more independently optimized ligands of different binding sites are combined to give a high-affmity binder. The example presented here deals with the development of a selective inhibitor for the protein tyrosine phosphatase IB (PTPlB).6i... 

Xie J, Comeau AB, Seto CT. Squaric acids a new motif for designing inhibitors of protein tyrosine phosphatases. Org. Lett. 2003 6 83-86. 

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