Molecular modeling unknown receptors

Objectives Optimize biological activity of drugs Find new active lead compounds Characteristics Response in isolated systems Effects are specific and well defined Specific mechanism of action Receptor is known in most cases Techniques Hansch Approach Multivariate Analysis Computerized molecular modeling Estimate rates of fate processes Analyze Processes Whole organism response Net effects (mortality growth, etc.) Specific nonspecific mechanisms Receptor unknown in most cases Hansch Approach Multivariate Analysis Molecular modeling not applied... 

Taste research has evolved considerably over the last years what will certainly result in new compounds and lead structures. The three approaches mentioned, i.e. TDA, receptor-based assays, and molecular modelling, are complementary methods (or tools) that may reveal new taste-active and taste-modifying compounds. The TDA method may especially help discovering taste modulators, because the corresponding receptors and processes are largely unknown. However, many other parameters must be checked, apart from technical taste testing, to evaluate the commercial potential of these new molecules, i.e. stability, safety, cost, availability, range of application, etc. Therefore, just a few molecules may succeed to be widely applied to culinary products. 

The nature of the receptors is yet unknown. Possibly it may be characterized at some time in the future in terms of a particular enzyme or by a definite molecular model. Biochemical isolation and identification of the receptors will be very difficult, of course, as the receptor is defined not only by its binding a drug molecule, but also by its eliciting a certain biological response. Therefiire, the biological reaction is used to advantage as a natural receptor-detector (Ahlquist). In other words, in studying receptors and their properties, mainly indirect methods are used. 

Three-dimensional database searching is a powerful new tool for developing novel synthetic targets. This technique can be used in cases where an enzyme/receptor 3-D structure is known, or alternatively in the case where the enzyme/receptor structure is unknown. In the latter case an active compound or series of compounds can be used to develop a pharmacophore model. Because 3-D database searching requires biological data stored in 2-D databases and molecular modelling techniques, we expect to see increased integration of 2-D and 3-D database/ information systems. 

Once in the serum, aluminium can be transported bound to transferrin, and also to albumin and low-molecular ligands such as citrate. However, the transferrrin-aluminium complex will be able to enter cells via the transferrin-transferrin-receptor pathway (see Chapter 8). Within the acidic environment of the endosome, we assume that aluminium would be released from transferrin, but how it exits from this compartment remains unknown. Once in the cytosol of the cell, aluminium is unlikely to be readily incorporated into the iron storage protein ferritin, since this requires redox cycling between Fe2+ and Fe3+ (see Chapter 19). Studies of the subcellular distribution of aluminium in various cell lines and animal models have shown that the majority accumulates in the mitochondria, where it can interfere with calcium homeostasis. Once in the circulation, there seems little doubt that aluminium can cross the blood-brain barrier. 

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