Drug Discovery Methods

An informative introduction to the concepts involved in drug discovery (Korfmacher 2005) also emphasizes the role played by LC-MS techniques. As discussed in that review, the discovery chain involves at least the following identifiable steps  

an in vitro passive permeability test performed early in the discovery process to rapidly screen (using LC-MS) the ability of these lead compounds to cross the intestinal barrier, a crucial step in the absorption of an oral dose of the drug candidate into the blood (the most common of these tests is that based on a human colon adrenocarcinoma cell line Caco-2)  

a screen to determine the potential of a candidate compound for drug-drug interactions by measuring the inhibition or induction of metabohsm of a standard set of compounds by the cytochrome P450 (CYP450) enzymes (this assay is unique in that it does not measure the concentration of the new drug candidate, but rather those of the suite of test compounds, so that it is not necessary to develop a new analytical method for each new candidate)  

an in vivo version of step 5. using laboratory animals (often a rat model) to indicate more closely the likely pharmacokinetics of the drug candidate (kinetics of absorption into and clearance from the blood and possibly also important body organs, i.e. absorption-distribution-mietabolism-excretion (ADME) studies) in humans  

identification of metabohtes and measurement of their rate of appearance and yield in excreta  

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Kitchen DB, Decornez H, Furr JR, Bajorath J. Docking and scoring in virtual screening for drug discovery methods and applications. Nat Rev Drug Discov 2004 3(ll) 935-49. 

Yan Q (2008) The integration of personalized and systems medicine bioinformatics support for pharmacogenomics and drug discovery. Methods Mol Biol 448 1-19... 

Researchers at Sunesis pharmaceuticals have developed a fragment-based drug discovery method termed tethering [25]. The approach, which is illustrated in Scheme 2.6, shares a number of features with DCC. Whereas protein-directed DCLs equilibrate small molecules via disulfide formation, say, in the presence of a protein that acts as a thermodynamic trap, tethering uses a cysteine residue on the protein surface to reversibly capture small-molecule thiol fragments from solution. Tethering is designed... 

Babine, R. E. and Abdel-Meguid, S. S., eds. (2004). Protein crystallography in drug discovery. Methods and Principles in Medicinal Chemistry, Vol. 20. Wiley-VCH. 

Waugh, S. M. and Fletterick, R. J. (2004). Crystalhzation and analysis of serine proteases with ecotin. In Protein Crystallography in Drug Discovery. Methods and Principles... 

Jurgen Moll and Riccardo Colombo (eds.), Target Identification and Validation in Drug Discovery Methods and Protocols, Methods in Molecular Biology, vol. 986, DO110.1007/978-1 -62703-311 -4 1, Springer Science+Business Media New York 2013... 

Ekins, S., Mestres, J., Testa, B. In silico pharmacology for drug discovery methods for virtual ligand screening and profiling. Br. J. Pharmacol. 2007, 152, 9-20. 

Although serendipity has been quite successful in drug design, it is a method that is difficult to reproduce. Accordingly, over the past fifty years, a variety of other drug discovery methods have been pioneered. 

Kopke, A. (2006). The proteomics toolbox—A review of the newest drug discovery methods. Business Briefing Future Drug Discovery. Touch Briefings, London, UK. 

Kitchen, D.B., Decornez, H., Furr, J.R., Bajorath, J. Docking and Scoring in Virtual Screening for Drug Discovery Methods and Applications. Nat. Rev. Drug Discov. 2004, 77, 935-949. 

G. Proetzel, M.V. Wiles (eds.), Mouse Models for Drug Discovery, Methods in Molecular Biology 602,... 

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