Bernard Testa

..The conclusion is that oxidoreductases are the main enzymes responsible for the formation of toxic or active metabolites, whereas transferases play the major role in producing inactive and nontoxic metabolites...

..We conclude that prodrugs offer a viable strategy to disentangle pharmacodynamic and pharmacokinetic optimization...

..Most significantly in an ADME perspective, the molecule is able, within the limits of its property space, to adapt to the medium. This is equivalent to saying that the medium constrains the molecule to resemble it as much as feasible...

..This increase in information content is interpreted as facilitated adaptability of the population...

..Thus, there is a need for several drug discovery scientists to better grasp the variety of drug metabolism reactions and enzymes and their consequences...

..In other words, variation acting alone progressively decreased the information content of a population. When both factors, F and Y, were applied simultaneously, their relative weight determined the progressive change in SE...

..g., flavin-containing monooxygenases, amine oxidases, molybdenum hydroxylases, peroxidases, and the innumerable dehydrogenases/reductases...

..New antimicrobial agents are also in the pipeline. In addition, biooxidative bioprecursors offer a promising strategy in specific cases, as illustrated by the successful antiaggregating agent clopidogrel...

..The predictions for four representative substrates are presented in detail (Figs. 1-4), illustrating the interest of such an evaluation in identifying where and how predictive rules can be improved...

..Nonenzymatic reactions, mainly of glutathione conjugation, also receive due attention. A number of medicinally, environmentally, and toxicologically relevant examples are presented and discussed...

..But, far from being concerned only with individual cases, the review is based on broad classifications, global rationalizations, and synthetic hypotheses...

..In other words, chemodiversity is the material condition for life to emerge and exist. Increasing our knowledge of chemodiversity is thus a condition for a better understanding of life as a process...

..The results of these simulations illustrate, in a graphically didactic manner, the influence of natural selection, operating through relative fitness, in the emergence and dominance of a fitter mutant...

..In conclusion, SULT1A3 is not substrate-enantioselective toward normetanephrine, an unexpected finding explainable by a mutual adaptability between the ligands and SULT1A3 through an "induced-fit model" in the catalytic pocket...

..CONCLUSIONS: Up to six permeation kinetics can be obtained per rat, and the method has shown to be a valuable tool to estimate human oral absorption...

..However, such models are more reliable when confined within well-defined chemical classes, and their applicability is often limited by the narrow property space of the set of permeants under study...

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..These findings have relevance to observations about the mechanism of action of nonspecific anesthetic agents...

..This study was undertaken to examine the MetaSite algorithm by comparing its predictions with experimentally characterized metabolites of statins produced by cytochromes P450 (CYPs)...

..Molecular sensitivity (namely, how much a given computable physicochemical property varies as a function of flexibility) appears as a promising descriptor to encode some of the information contained in molecular property spaces...

..This finding suggests that the selectivity profile of acetylcholine for the M(2) receptor is largely entropy-driven, a fact that might explain the intrinsic difficulty to design subtype-selective muscarinic agonists...

..e., binding score) of carnosine to the catalytic site. This is one of the first reports documenting the molecular mechanism of an allosteric enzyme activator using MD simulations...

..Solvent constraints on the property space clearly indicate that a polar medium tends to favor polar conformers, whereas the opposite is true for a solvent of low polarity...

..This work examines the lipophilic behavior of various zwitterions and shows how distribution profiles in biphasic systems and ionic partition diagrams may improve our understanding of pH-absorption profiles of drugs...

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