Molecular mechanism of action

The process of pore-formation comprises a coordinated series of molecular events that often can be distinguished and dissociated from each other by using functionally defective mutant proteins (see e.g. Bayley, 1994b Valeva et al., 1996 Walker and Bayley (1994 Walker et al., 1995). 

Binding studies have only been undertaken with alpha-toxin (Cassidy and Harshman, 1976 Hildebrand etai, 1991), aerolysin (Howard and Buckley, 1982), streptolysin O (Palmer etal., 1993) and perfringolysin 

Present on rabbit erythrocytes, but not identified not absolutely required for toxin binding to lipid bilayers 

Binding site on toxin molecule probably conformational and may involve C- and N-terminal halves of the molecule maximal binding at 20—25°C no dependency on metal ions 

---

Absorption, metaboHsm, and biological activities of organic compounds are influenced by molecular interactions with asymmetric biomolecules. These interactions, which involve hydrophobic, electrostatic, inductive, dipole—dipole, hydrogen bonding, van der Waals forces, steric hindrance, and inclusion complex formation give rise to enantioselective differentiation (1,2). Within a series of similar stmctures, substantial differences in biological effects, molecular mechanism of action, distribution, or metaboHc events may be observed. Eor example, (R)-carvone [6485-40-1] (1) has the odor of spearrnint whereas (5)-carvone [2244-16-8] (2) has the odor of caraway (3,4). 

FIGURE 10.24 Simulation data set fit to an allosteric model (Equation 7.6 panel a) and to an orthosteric model (Equation 6.31 panel b). The data points circled with the dotted line were altered very slightly to cause the sum of squares for computer fit of the points to the model to favor either the allosteric or orthosteric model. It can be seen that very small differences can support either model even though they describe completely different molecular mechanisms of action. 

Diltiazem is the only benzothiazepine in clinical use. Its molecular mechanism of action as well as its pharmacological effects closely resemble those of phenylalkylamines. 

The cellular/molecular mechanism of action for these cyclic peptide toxins is now an area of active research in several laboratories. These peptides cause striking ultrastructural changes in isolated hepatocytes (95) including a decrease in the polymerization of actin. This effect on the cells cytoskeletal system continues to be investigated and recent work indirectly supports the idea that these toxins interact with the cells cytoskeletal system (86,96). Why there is a specificity of these toxins for liver cells is not clear although it has been suggested that the bile uptake system may be at least partly responsible for penetration of the toxin into the cell (92). 

Note that the dried rhizome of Cimicifuga racemosa (British Pharmaceutical Codex, 1934 black cohosh) has been used as a bitter and mild expectorant in the form of a liquid alcoholic extract (1 in 1 dose 0.3-2 mL) and is sold as alternative remedy for the treatment of menopausal syndrome at dose of 40-80 mg/day. The active constituents of black cohosh, and, therefore, the precise molecular mechanism of action involved in the climacteric property of Cimicifuga racemosa, are still unknown. The most recent data suggest that the plant is not estrogenic sensu stricto (126). 

Research in PAH carcinogenesis has made major advances in the past decade. Most notable has been identification of diol epoxide metabolites as the active forms of benzo[a]pyrene, 7,12-dimethylbenz[tf]anthracene, and other carcinogenic PAH. This finding has stimulated enormous research activity and opened the way to determination of the detailed molecular mechanism of action of this important class of carcinogenic molecules. 

Cazarolli LH, Zanatta L, Alberton EH, Figueredo MS, Folador P, Damazio RG, Pizzolatti MG and Silva FR. 2008. Flavonoids cellular and molecular mechanisms of action in glucose homeostasis. Mini Rev Med Chem 8(10) 1032-1038. 

McDonnell DP, Wijayarate A, Chang C, Norris JD (2002) Elucidation of the molecular mechanism of action of selective estrogen receptor modulators. Am J Cardiol 0(suppl) 35F-43F... 

Tsai MJ, O Malley BW (1994) Molecular mechanisms of action of steroid/thyroid receptor superfamiliy members. Annu Rev Biochem 63 451-486... 

Ignarro, L. J., After 130 years, the molecular mechanism of action of nitroglycerin is revealed. Proc. Natl. Acad. Sci. USA 99 (2002),... 

Benz, R. and McLaughlin, S. (1983). The molecular mechanism of action of the proton ionophore FCCP (carbonyl cyanide p-trifluoromethoxyphenylhydrazone), Biophys. J., 41, 381-398. 

Molecular mechanics (MM), 16 727, 741-743 studies of, 26 104 Molecular mechanism of action, identifying, 27 646... 

Despite the many decades amyl nitrite and glyceryl trinitrate have been used in therapy, it is only in recent years that the molecular mechanism of action of the nitrovasodilators has begun to be understood [3-5]. The drugs act by releasing nitric oxide (NO, a neutral radical usually written simply as NO), which produces smooth muscle relaxation in blood vessels and exhibits a range of other biological effects [6]. Thus, bioactivation to yield NO precedes the main therapeutic effect of nitrovasodilators and would justify their classifica-... 

Boquet, P., Munro, P., Fiorentini, C. and Just, I., Toxins from anaerobic bacteria specificity and molecular mechanism of action, Curr. Opin. Microbiol., 1, 66-74, 1998. 

The clinical effects of chloroform toxicity on the central nervous system are well documented. However, the molecular mechanism of action is not well understood. It has been postulated that anesthetics induce their action at a cell-membrane level due to lipid solubility. The lipid-disordering effect of chloroform and other anesthetics on membrane lipids was increased by gangliosides (Harris and Groh 1985), which may explain why the outer leaflet of the lipid bilayer of neuronal membranes, which has a large ganglioside content, is unusually sensitive to anesthetic agents. Anesthetics may affect calcium-dependent potassium conductance in the central nervous system (Caldwell and Harris 1985). The blockage of potassium conductance by chloroform and other anesthetics resulted in depolarization of squid axon (Haydon et al. 1988). 

General anesthetic drugs have the ability to reduce the level of consciousness in a dose dependent fashion. The study of the neurobiological mechanisms of action of these drugs may provide insight into the systems that are necessary for the existence of consciousness. It clearly cannot be assumed however, that the systems that underlie the action of these substances are in themselves sufficient for consciousness. Indeed, within a complex neural network, any number of small alterations can disturb the whole. This chapter focuses on what is known about the molecular mechanism of action of drugs that are used clinically for general anesthesia. 

Andersen PH The dopamine uptake inhibitor GBR 12909 selectivity and molecular mechanism of action. Fur J Pharmacol 166 493-504, 1989 Andersen PH, Geisler A Lithium inhibition of forskohn-stimulated adenylate... 

Increasing the knowledge about a compound to include molecular mechanism of toxicity, in addition to molecular mechanisms of action, should lead to improved pre-clinical and clinical lead selection and facilitate improved clinical trial designs with the ultimate outcome of obtaining more selective and less toxic drugs. 

The organophosphate inhibitors are sometimes referred to as "irreversible" cholinesterase inhibitors, and edrophonium and the carbamates are considered "reversible" inhibitors because of the marked differences in duration of action. However, the molecular mechanisms of action of the three groups do not support this simplistic description. 

Ito et al A molecular mechanism of action of theophylline Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci USA 2002 99 8921. [PMID 12070353]... 

---