Quantifying Biological Activity in Chemical Terms: A Pharmacology Primer to Describe Drug Effect Export

@article{Kenakin09, abstract = {doi: 10.1021/cb800299s Drugs can initiate, inhibit, modulate or potentiate basal activity in cells to produce physiological effect. This complex interface generates behaviors for drugs in different tissues that can cause apparently capricious variation between tissues under various physiological conditions; this poses a problem for pharmacologists studying drugs in test systems to predict effects in therapeutic ones. De-emphasis of tissue-specific drug behaviors by reducing drug effect to chemical terms can, to a large extent, reduce the effects of variances in biological systems (i.e. changing basal setpoints, genetic and biochemical variability etc.). This paper discusses the application of four major pharmacodynamic parameters (affinity, efficacy, orthosteric vs allosteric binding, rate of dissociation of drug from the biological target) to the quantification of biological activity to furnish chemical structure-activity relationships (SAR). These four parameters can be used to quantify effect in test systems and predict subsequent activity in a therapeutic setting. Since there are at least three different SAR?s involved in the drug discovery process (primary therapeutic activity, pharmacokinetics and safety), with more possible if target selectivity is required, some simple statistical approaches to multi-variate structure-activity studies (i.e. primary activity + selectivity data) also are considered. In total, these data can provide system independent data to characterize biological activity of molecules in chemical terms that can greatly reduce biologically-induced variability.}, author = {Kenakin, Terry}, citeulike-article-id = {4160782}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/cb800299s}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/cb800299s}, doi = {10.1021/cb800299s}, journal = {ACS Chemical Biology}, keywords = {affinity, allosteric, efficacy, kinetics, orthosteric, sar}, number = {ja}, posted-at = {2009-03-10 15:57:16}, priority = {2}, title = {Quantifying Biological Activity in Chemical Terms: A Pharmacology Primer to Describe Drug Effect}, url = {http://dx.doi.org/10.1021/cb800299s}, volume = {0}, year = {0000} }

TY - JOUR ID - Kenakin09 L3 - citeulike-article-id:4160782 N2 - doi: 10.1021/cb800299s Drugs can initiate, inhibit, modulate or potentiate basal activity in cells to produce physiological effect. This complex interface generates behaviors for drugs in different tissues that can cause apparently capricious variation between tissues under various physiological conditions; this poses a problem for pharmacologists studying drugs in test systems to predict effects in therapeutic ones. De-emphasis of tissue-specific drug behaviors by reducing drug effect to chemical terms can, to a large extent, reduce the effects of variances in biological systems (i.e. changing basal setpoints, genetic and biochemical variability etc.). This paper discusses the application of four major pharmacodynamic parameters (affinity, efficacy, orthosteric vs allosteric binding, rate of dissociation of drug from the biological target) to the quantification of biological activity to furnish chemical structure-activity relationships (SAR). These four parameters can be used to quantify effect in test systems and predict subsequent activity in a therapeutic setting. Since there are at least three different SAR?s involved in the drug discovery process (primary therapeutic activity, pharmacokinetics and safety), with more possible if target selectivity is required, some simple statistical approaches to multi-variate structure-activity studies (i.e. primary activity + selectivity data) also are considered. In total, these data can provide system independent data to characterize biological activity of molecules in chemical terms that can greatly reduce biologically-induced variability. IS - ja JF - ACS Chemical Biology TI - Quantifying Biological Activity in Chemical Terms: A Pharmacology Primer to Describe Drug Effect VL - 0 KW - affinity KW - allosteric KW - efficacy KW - kinetics KW - orthosteric KW - sar AU - Kenakin, Terry PY - 2000/// UR - http://dx.doi.org/10.1021/cb800299s ER -