Activation molecular basis

Adverse activity Molecular basis Structural component Effect of structural optimization Impact if dose limiting on candidate progression... 

The data obtained suggest that the increase in SAH content in liver of vitamin Bs-deficient mice and rats is not due only to decrease in cystathionine synthase activity. Molecular basis for SAH metabolic disturbances under condition of vitamin B5-deficency remain to be clarified. 

P. Crabbe, Top..Stereochem. 1 93 (1967) C. Djerassi, Optical Rotatory Dispersion, McGraw-Hill, New Vbrk, 1960 P. Crabbe, Optical Rotatory Dispersion and Circular Dichroism in Organic Chemistry, Holden D, San Francisco, 1965 E. Chamey, The Molecular Basis of Optical Activity. Optical Rotatory Dispersion and Circular Dichroism, John Wiley Sons, New Vbrk, 1979. 

ET-1 also stimulates anti-apoptotic signal cascades in fibroblasts, vascular smooth muscles and endothelial cells (via phosphatidylinositol-3-kinase and Akt/pro-tein kinase B). In prostate and ovarian cancer, upregulation of endothelin synthesis and ETA receptors has been associated with a progression of the disease. The inhibiton of ETA receptors results in a reduced tumour growth. In malignant melanoma, ETB receptors are associated with tumour progression. Endothelins can also stimulate apoptosis in stretch-activated vessels via the ETB receptor, which contrasts the above-mentioned effects. The molecular basis for these differential anti- and pro-apoptotic reactions mediated by endothelins remains elusive. 

Several possible models can be discussed for the molecular basis of slow inhibition, but experimental evidence in support of one or the other is still lacking for glycosidases. A reversible chemical reaction at the active site, for example, formation of the cyclic imine 3 or a diffusion-controlled association with a trace of 3 in equilibrium with the 5-araino-5-deoxypyranose 1 can be precluded, because slow inhibition is also observed with 1-deoxynojirimycin and its analogs and with acarbose (see Section II,2,d) and indoli-... 

Various statistical treatments of reaction kinetics provide a physical picture for the underlying molecular basis for Arrhenius temperature dependence. One of the most common approaches is Eyring transition state theory, which postulates a thermal equilibrium between reactants and the transition state. Applying statistical mechanical methods to this equilibrium and to the inherent rate of activated molecules transiting the barrier leads to the Eyring equation (Eq. 10.3), where k is the Boltzmann constant, h is the Planck s constant, and AG is the relative free energy of the transition state [note Eq. (10.3) ignores a transmission factor, which is normally 1, in the preexponential term]. 

Tomasz, M. Palom, Y. The mitomycin bioreductive antitumor agents cross-linking and alkylation of DNA as the molecular basis of their activity. Pharmacol. Ther. 1997, 76, 73-87. 

Despite its widespread use in therapy as an anticoagulant and antilipe-mic agent, several aspects of the structure and physiological function of heparin remain obscure. However, active reseach has now contributed to a better understanding of the molecular basis for the pharmacological activity of this polysaccharide. 

K8. Kanno, H., Fujii, H., Tsujino, G., and Miwa, S., Molecular basis of impaired pyruvate kinase isozyme conversion in erythroid cells A single amino acid substitution near the active site and decreased mRNA content of the R-type PK. Biochem. Biophys. Res. Commun. 192, 46-52... 

Makriyannis A, Rapaka RS. The molecular basis of cannabinoid activity. Life Sci 1990 24 2173-2184. 

Weinstein, H., R. Osman, and J. P. Green. 1979. The Molecular Basis of Structure-Activity Relationships Quantum Chemical Recognition Mechanisms in Drug-Receptor Interactions. In Computer-Assisted Drug Design. E. C. Olson and R. E. Christofferson, eds. American Chemical Society, Washington, D.C. 

A better understanding of the molecular basis of nitrosoureas activity is obtained by complementing experimental data with ab initio calculations. 

Not all type I interferons induce exactly the same range of responses, and the antiviral to antiproliferative activity ratio differs from one type I interferon to another. As all bind the same receptor, the molecular basis by which variation in biological activities is achieved is poorly understood as yet. 

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