Drug discovery evaluation

Gibbs, J. P., Hyland, R., and Youdim, K. (2006) Minimizing polymorphic metabolism in drug discovery evaluation of the utility of in vitro methods for predicting pharmacokinetic consequences associated with CYP2D6 metabolism. Drug Metab. Dispos. 34, 1516-1522. 

Tondi D, Costi MR Enhancing the drug discovery process by integration of structure-based design and combinatorial synthesis. In Viswanadhan AK, Chose VN, editors. Combinatorial library design and evaluation. New York Marcel Dekker, 2001. p. 563-604. 

Parrott, N Paquereau, N Coassolo, P Lave, Th. An evaluation of the utility of physiologically based models of pharmacokinetics in early drug discovery. f Pharm. Sci. 2005, 94, 2327-2343. 

Hou, T. J., Xu, X. J. ADME evaluation in drug discovery. 3. Modeling blood-brain barrier partitioning using simple molecular descriptors. /. Chem. Inf. Model. 2003, 43, 2137-2152. 

Liu, R., So, S.-S. Development of quantitative structure-property relationship models for early ADME evaluation in drug discovery. 1. Aqueous solubility./. Chem. Inf. Comp. Set. 2001, 41, 1633-1639. 

Once potent ligands for a viral protein are identified, further advancement depends on demonstrating activity in cells. Unfortunately, reproducible in vitro viral replication assays for HCV have not been reported. There are scattered reports that a very low level of genome replication, or even virus production, can be observed under certain circumstances [56]. However, recently specific sequences yielding relatively reproducible replication, at consistently detectable levels have been reported [57]. In the coming years these may allow routine assays suitable for compound evaluation to be developed, but to date drug discovery must rely on other cell culture models. 

Evaluation of Enzyme Inhibitors in Drug Discovery, by Robert A. Copeland ISBN 0-471-68696-4 Copyright 2005 by John Wiley Sons, Inc. 

While the main focus of this chapter has been on enzymes as the primary molecular targets of drug action, it is worthwhile noting that the quantitative evaluation of enzyme activity has other important roles in drug discovery and development. 

Examples of such systems include the reactions of kinases, phosphatases, hydroxylases, acetylases, ubiquitin transferases, and many other enzyme classes that represent attractive targets for drug discovery. There are several mechanisms by which an enzyme can catalyze these types of reactions, and the details of the mechanism are important in determining the best approach to designing activity assays for the enzyme and for proper evaluation of inhibitors that are identified through those activity assays. 

---