Biological responses, classifications

Elucidation of the stmctural requirements for dmg interaction at the recognition site is by the study of stmcture—activity relationships (SAR), in which, according to a specific biologic response, the effects of systematic molecular modification of a parent dmg stmcture are determined. Such studies have permitted the classification of discrete classes of pharmacological receptors. For example, the neurotransmitter acetylcholine acts at both peripheral and central receptors which are of at least three distinct types. The effects of acetylcholine are mimicked in smooth and cardiac muscles and secretory... 

Once again we come upon a chemical classification that has no pharmacological significance. The three drugs in this small group cause widely different biological responses. 

Some of the examples and discussion in this chapter draw on the two-class classification problem, which here is hit versus inactive . The word active refers to a validated hit, that is, a molecule that truly does exhibit some level of the desired biological response. A key point is that an assay is itself an estimator. With this in mind, definitions and a discussion of error rates are given in the context of predictive models. Borrowing from the terminology of signal detection, the sensitivity of a model refers to the fraction of observed hits that are classified as (or predicted to be) hits by the model, and specificity refers to the fraction of observed inactives classified as inactives by the model. An observed hit is not necessarily an active molecule, but simply a molecule for which the primary screening result exceeded a decision threshold. Whether such a molecule turns out to be an active is a problem that involves the sensitivity of the assay, but the task at hand is for... 

Figure 6 Classification of GPCR ligands GPCR ligands can be divided into three classes agonists (panel a), which increase the proportion of active receptor states to cause a biological response inverse agonists (panel a), which decrease the proportion of active receptor states to reduce constitute (basal) activity and antagonists (panel bj, which inhibit the action of other ligands...

Figure 21.5 Strategies for understanding nanomaterial enviromnental health and safely, toxicity and biological response include nanomaterial classihcalion, that is, compositional classification (metal, metal oxide, polymer, senticonductor, carbon-based, etc.) for a material that has one dimension between 1 and 100 mn chentical composition in terms of bulk and surface size considerations, primary and secondary (aggregate) sizes and geometric structure which includes shape and porosity.

The fir.-fit line of the file (see Figure 2-110) - the HEADER record - hold.s the moleculc. s classification string (columns 11-50), the deposition date (the date when the data were received by the PDB) in columns 51-59, and the PDB (Dcode for the molecule, which is unique within the Protein Data Bank, in columns 63-66. The second line - the TITLE record - contains the title of the experiment or the analysis that is represented in the entry. The subsequent records contain a more detailed description of the macromolecular content of the entiy (COMPND), the biological and/or chemical source ofeach biological molecule in the entiy (SOURCE), a set ofkeywords relevant to the entiy (KEYWDS). information about the experiment (EXPDTA), a list of people responsible for the contents of this entiy (.AUTHOR), a history of modifications made to this entiy since its release (REVDAT), and finally the primaiy literature citation that describes the experiment which resulted in the deposited dataset ()RNL). 

Initial classification of some cytokines was also undertaken on the basis of the specific biological activity by which the cytokine was first discovered (e.g. TNF exhibited cytotoxic effects on some cancer cell lines CSFs promoted the growth in vitro of various leukocytes in clumps or colonies). This, too, proved an unsatisfactory classification mechanism, as it was subsequently shown that most cytokines display a range of biological activities (e.g. the major biological function of TNF is believed to be as a regulator of both the immune and inflammatory response). More recently, primary sequence analysis of cytokines coupled to determination of secondary and tertiary structure reveal that most cytokines can be grouped into one of six families (Table 8.2). 

In the area of bioengineered products, many of which are complex proteins of potent but sparsely studied activities in living systems, the investigative responsibilities of the toxicologist are likely to be very important, because he/she may be the first observer able to study the effects of repeated administration of a range of doses on a living system. It is now possible to frame a classification of the types of biologically derived therapeutic products (Table 12.3). 

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