Overview of Drug Discovery and Development

Mark A. Ator1, John P. Mallamo1, Michael Williams1

1 Cephalon, Inc., West Chester, Pennsylvania
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 9.9
DOI:  10.1002/0471141755.ph0909s35
Online Posting Date:  December, 2006
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library

Abstract

This overview unit describes the core activities involved in the drug discovery and development process, from target identification ‐ including preclinical biology, medicinal and process chemistry ‐ to pharmacokinetics and metabolism (ADME), and also activities related to the to the drug approval process. The latter include the activities related to the filing of an IND (Investigational New Drug) application and also Phases I – III of clinical trials that form the basis of an NDA (New Drug Application) submission, as well as post‐marketing Phase IV activities as required by the U.S. Food and Drug Administration (FDA) and the European and Japanese counterparts

     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Table of Contents

  • Introduction
  • Pharmacology
  • Medicinal Chemistry
  • Drug Discovery
  • Drug Targets
  • Lead Discovery
  • Compound Sources
  • Biologicals, Antisense, and RNA Interference
  • Computational Chemistry
  • High‐Throughput Screening
  • Hit to Lead
  • Lead Optimization
  • Structure‐Activity Relationships (SARs)
  • Drug Metabolism and Pharmacokinetics
  • Preclinical Development
  • Literature Cited
  • Figures
  • Tables
     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Materials

GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Figures

Videos

Literature Cited

Literature Cited
   Ator, M.A. and Williams, M. 2005. Safety Pharmacology III: Target profiling. In xPharm (S.J. Enna and D.B. Bylund, executive editors). Elsevier‐MDL, New York. http://www.xpharm.com/citation?Article_ID=119484.
   Avdeef, A. 2001. Physicochemical profiling: Solubility, permeability and charge state. Curr. Top. Med. Chem. 1:277‐351.
   Becker, O.M., Marantz, Y., Shacham, S., Inbal, B., Heifetz, A., Kalid, O., Bar‐Haim, S, Warshaviak, D., Fichman, M., and Noiman, S. 2004. G protein‐coupled receptors: In silico drug discovery in 3D. Proc. Natl. Acad. Sci. U.S.A. 101:11304‐11309.
   Bevan, C.D. and Lloyd, R.S. 2000. A high‐throughput screening method for the determination of aqueous drug solubility using laser nephelometry in microtiter plates. Anal. Chem. 72:1781‐1787.
   Binder, S., Levitt, A.M., Sacks, J.J., and Hughes, J.M. 1999. Emerging infectious diseases: Public health issues for the 21st Century. Science 284:1311‐1313.
   Bleicher, K.H., Bohm, H.J., Muller, K., and Alanine, A.I. 2003. Hit and lead generation: Beyond high‐throughput screening. Nat. Rev. Drug Discov. 2:369‐378.
   Bohets, H., Annaert, P., Mannens, G., Van Beijsterveldt, L., Anciaux, K., Verboven, P., Meuldermans, W., and Lavrijsen, K. 2001. Strategies for absorption screening in drug discovery and development. Curr. Top. Med. Chem. 1:367‐383.
   Bultinck, P.H., DeWinter, H., Langenaeker, W., and Tollenaere, J.P. 2004. Computational Medicinal Chemistry for Drug Discovery. Marcel Dekker, New York.
   Caricasole, A., Bakker, A., Copani, A., Nicoletti, F., Gaviraghi, G., and Terstappen, G.C. 2005. Two sides of the same coin: Wnt signaling in neurodegeneration and neuro‐oncology. Biosci. Rep. 25:309‐327.
   Carney, S. 2005. How can we avoid the productivity gap? Drug Disc. Today 10:1011‐1013.
   Chakravarty, S. and Dugar, S. 2002. Inhibitors of p38α MAP kinase. Ann. Rep. Med. Chem. 37:177‐186.
   Chang, R.S., Lotti, V.J., Monaghan, R.L., Birnbaum, J., Stapley, E.O., Goetz, M.A., Albers‐Schonberg, G., Patchett, A.A., Liesch, J.M., Hensens, O.D., and Springer, J.P. 1985. A potent nonpeptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus alliaceus, Science 230:177‐179.
   Chiu, P.J., Marcoe, K.F., Bounds, S.E., Lin, C.H., Feng, J.J., Lin, A., Cheng, F.C., Crumb, W.J., and Mitchell, R. 2004. Validation of a [3H]astemizole binding assay in HEK293 cells expressing HERG K+ channels. J. Pharmacol. Sci. 95:311‐319.
   Chow, S.‐C. and Liu, J.‐P. 2004. Design and Analysis of Clinical Trials: Concepts and Methodologies. 2nd ed., Wiley Interscience, Hoboken, N.J.
   Collins, F.S., Green, E.D., Guttmacher, A.E., Guyer, M.S., and the U.S. National Human Genome Research Institute. 2003. A vision for the future of genomics research. Nature 422:835‐847.
   Copeland, R.E. 2005. Evaluation of Enzyme Inhibitors in Drug Discovery. Wiley Interscience, Hoboken, N.J.
   Costanzo, M.J., Almond, H.R., Jr., Hecker, L.R., Schott, M.R., Yabut, S.C., Zhang, H.C., Andrade‐Gordon, P., Corcoran, T.W., Giardino, E.C., Kauffman, J.A., Lewis, J.M., de Garavilla, L., Haertlein, B.J., and Maryanoff, B.E. 2005. In‐depth study of tripeptide‐based alpha‐ketoheterocycles as inhibitors of thrombin: Effective utilization of the S1′ subsite and its implications to structure‐based drug design. J. Med. Chem. 48:1984‐2008.
   Crespi, C.L., Miller, V.P., and Stresser, D.M. 2002. Design and application of fluorometric assays for human cytochrome P450 inhibition. Methods Enzymol. 357:276‐84.
   Daly, J.W., Garraffo, H.M., Spande, T.F., Decker, M.W., Sullivan, J.P., and Williams, M. 2000. Alkaloids from frog skin: The discovery of epibatidine and the potential for developing novel non‐opioid analgesics. Nat. Prod. Rep. 17:131‐135.
   Davis, A.M., Keeling, D.J., Steele, J., Tomkinson, N.P., and Tinker, A.C. 2005. Components of successful lead generation. Curr. Top. Med. Chem. 5:421‐439.
   Dean, M.K., Higgs, C., Smith, R.E., Bywater, R.P., Snell, C.R., Scott, P.D., Upton, G.J., Howe, T.J., and Reynolds, C.A. 2001. Dimerization of G‐protein‐coupled receptors. J. Med. Chem. 44:4595‐4614.
   Di, L., Kerns, E.H., Fan, K., McConnell, O.J., and Carter, G.T. 2003. High throughput artificial membrane permeability assay for blood‐brain barrier. Eur. J. Med. Chem. 38:223‐232.
   DiMasi, J.A., Hansen, R.W., and Grabowski, H.G. 2003. The price of innovation: New estimates of drug development costs. J. Health Econ. 22:151‐185.
   Drews, J. 2000. Drug discovery: A historical perspective. Science 287:1960‐1964.
   Estibeiro, P. and Godfray, J. 2001. Antisense as a neuroscience tool and therapeutic agent. Trends Neurosci. 24:S56‐S62.
   European Agency for the Evaluation of Medicinal Products. 2000. ICH S7A: Safety Pharmacology studies for human pharmaceuticals. European Agency for the Evaluation of Medicinal Products. Evaluation of Medicines for Human Use CPMP/ICH/539/00, London, 16 November 2000.
   Evans, B.E., Rittle, K.E., Bock, M.G., DiPardo, R.M., Freidinger, R.M., Whitter, W.L., Gould, N.P., Lundell, G.F., Homnick, C.F., Veber, D.F., Anderson, P.S., Chang, R.S.L., Lotti, V.J., Cerino, D.J., Chen, T.B., King, P.J., Kunkel, K.A., Springer, J.P., and Hirshfeld, J. 1987. Design of nonpeptidal ligands for a peptide receptor: cholecystokinin antagonists. J. Med. Chem. 30:1229‐1239.
   Flamand, N., Meunier, J., Meunier, P., and Agapakis‐Causse, C. 2001. Mini mutagenicity test: A miniaturized version of the Ames test used in a prescreening assay for point mutagenesis assessment. Toxicol. In Vitro 15:105‐114.
   Gad, S.C. 2002. Drug Safety Evaluation. Wiley Interscience, New York.
   Gee, C.E. and Mansuy, I.M. 2005. Protein phosphatases and their potential implications in neuroprotective processes. Cell Mol. Life Sci. 62:1120‐1130.
   Gillespie, P. and Goodnow, R.A. Jr. 2004. The hit‐to‐lead process in drug discovery. Ann. Rep. Med. Chem. 39:293‐304.
   Gooding, O.W. 2004. Process optimization using combinatorial design principles: Parallel synthesis and design of experiment methods. Curr. Opin. Chem. Biol. 8:297‐304.
   Gorre, M.E., Mohammed, M., Ellwood, K., Hsu, N., Paquette, R., Rao, P.N., and Sawyers, C.L. 2001. Clinical resistance to STI‐571 cancer therapy caused by BCR‐ABL gene mutation or amplification. Science 293:876‐880.
   Heijne, W.H., Kienhuis, A.S., van Ommen, B., Stierum, R.H., and Groten, J.P. 2005. Systems toxicology: Applications of toxicogenomics, transcriptomics, proteomics and metabolomics in toxicology. Expert Rev. Proteomics 2:767‐768.
   Hidalgo, I.J., Raub, T.J, and Borchardt, R.T. 1989. Characterization of the human colon carcinoma cell line (Caco‐2) as a model system for intestinal epithelial permeability. Gastroenterology 96:736‐749.
   Hill, R. 2000. NK1 (substance P) receptor antagonists: Why are they not analgesic in humans? Trends Pharmacol. Sci. 21:244‐246.
   Hodgson, J. 2001. ADMET: Turning chemicals into drugs. Nat. Biotech. 19:722‐726.
   Hop, C.E., Wang, Z., Chen, Q., and Kwei, G., 1998. Plasma‐pooling methods to increase throughput for in vivo pharmacokinetic screening. J. Pharm. Sci. 87:901‐903.
   Hutzler, M., Messing, D.M., and Wienkers, L.C. 2005. Predicting drug‐drug interactions in drug discovery: Where are we now and where are we going?. Curr Opin. Drug Discov. Devel. 8:51‐58.
   In Vivo Pharmacology Training Group. 2002. The fall and rise of in vivo pharmacology. Trends Pharmacol. Sci. 23:13‐18.
   International Council on Harmonization (ICH) S7B Guideline. 2004. The non‐clinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. ICH, Geneva. http://www.ich.org/LOB/media/MEDIA2192.pdf.
   Janzen, W.P. (ed.) 2002. High throughput screening: Methods and protocols. In Methods in Molecular Biology, Vol. 190. Humana Press, Totowa, N.J.
   Johnston, G.A. 2005. GABAA receptor channel pharmacology. Curr. Pharm. Des. 11:1867‐1885.
   Jorgensen, W.L. 2004. The many roles of computation in drug discovery. Science 303:1813‐1818.
   Kansy, M., Senner, F., and Gubernator, K. 1998. Physicochemical high throughput screening: Parallel artificial membrane permeation assay in the description of passive absorption processes. J. Med. Chem. 41:1007‐1010.
   Kelder, J., Grootenhuis, P.D., Bayada, D.M., Delbressine, L.P., and Ploemen, J.P. 1999. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm. Res. 16:1514‐1519.
   Kempf, D.J., Sham, H.L., Marsh, K.C., Flentge, C.A., Betebenner, D., Green, B.E., McDonald, E., Vasavanonda, S., Saldivar, A., Wideburg, N.E., Kati, W.M., Ruiz, L., Zhao, C., Fino, L., Patterson, J., Molla, A., Plattner, J.J., and Norbeck, D.W. 1998. Discovery of Ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy. J. Med. Chem. 41:602‐617.
   Kenakin, T. 2003. Predicting therapeutic value in the lead optimization phase of drug discovery, Nature Rev. Drug Discov. 2:429‐438
   Kenakin, T.A. 2004. Pharmacology Primer: Theory, Application and Methods. Elsevier Academic Press, San Diego.
   Kerns, E.H. and Di, L. 2005. Physicochemical profiling: Overview of the screens. Drug Disc. Today: Technologies 1:343‐348.
   Khan, A., Khan, S.R., Walens, G., Kolts, R., Giller, E.L. 2003. Frequency of positive studies among fixed and flexible dose antidepressant clinical trials: An analysis of the Food and Drug Administraton summary basis of approval reports. Neuropsychopharmacology 28:552‐557.
   Kola, I. and Landis, J. 2004. Opinion: Can the pharmaceutical industry reduce attrition rates? Nature Rev. Drug Discov. 3:711‐716.
   Kopec, K.K., Bozyczko‐Coyne, D., and Williams, M. 2005. Target identification and validation in drug discovery: the role of proteomics. Biochem. Pharmacol. 69:1133‐1139.
   Kubinyi, H. 2003. Drug research: Myths, hype and reality. Nat. Rev. Drug. Discovery 2:665‐668.
   Lander, E.S., Linton, L.K., Birren, B., Nusbaum, C., Zody, M.C., Baldwin, J. et al. 2001. Initial sequencing and analysis of the human genome. Nature 409:860‐921.
   Lefkowitz, R.J. 2004. Historical review: A brief history and personal retrospective of seven‐transmembrane receptors. Trends Pharmacol. Sci. 25:413‐422.
   Leist, M., Ghezzi, P., Grasso, G., Bianchi, R., Villa, P., Fratelli, M., Savino, C., Bianchi, M., Nielsen, J., Gerwien, J., Kallunki, P., Larsen, A.K., Helboe, L., Christensen, S., Pedersen, L.O., Nielsen, M., Torup, L., Sager, T., Sfacteria, A., Erbayraktar, S., Erbayraktar, Z., Gokmen, N., Yilmaz, O., Cerami‐Hand, C., Xie, Q.W., Coleman, T., Cerami, A., and Brines, M. 2004. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305:239‐242.
   Li, A.P., Gorycki, P.D., Hengstler, J.G., Kedderis, G.L., Koebe, H.G., Rahmani, R., de Sousas, G., Silva, J.M., and Skett, P. 1999. Present status of the application of cryopreserved hepatocytes in the evaluation of xenobiotics: consensus of an international expert panel. Chem. Biol. Interact. 121:117‐123.
   Lipinski, C.A., Lombardo, F., Dominy, B.W., and Feeney, P.J. 1997. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug. Deliv. Rev. 23:3‐25.
   Lloyd, G.K. and Williams, M. 2000. Neuronal nicotinic acetylcholine receptors as novel drug targets. J. Pharmacol. Exp. Ther. 292:461‐467.
   Luo, G., Cunningham, M., Kim, S., Burn, T., Lin, J., Sinz, M., Hamilton, G., Rizzo, C., Jolley, S., Gilbert, D., Downey, A., Mudra, D., Graham, R., Carroll, K., Xie, J., Madan, A., Parkinson, A., Christ, D., Selling, B., LeCluyse, E., and Gan, L.S. 2002. CYP3A4 induction by drugs: Correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab. Dispos. 30:795‐804.
   Lutz, M. and Kenakin, T.P. 1999. Quantitative Molecular Pharmacology and Informatics In Drug Discovery. John Wiley & Sons, Chichester, U.K.
   MacCoss, M. and Baillie, T.A. 2004. Organic chemistry in drug discovery. Science 303:1810‐1813.
   Maghazachi, A.A. 2005. Insights into seven and single transmembrane‐spanning domain receptors and their signaling pathways in human natural killer cells. Pharmacol. Rev. 57:339‐357.
   Manley, P.W., Bold, G., Bruggen, J., Fendrich, G., Furet, P., Mestan, J., Schnell, C., Stolz, B., Meyer, T., Meyhack, B., Stark, W., Strauss, A., and Wood, J. 2004. Advances in the structural biology, design and clinical development of VEGF‐R kinase inhibitors for the treatment of angiogenesis. Biochim. Biophys. Acta 1697:17‐27.
   Masson, J., Sagne, C., Hamon, M., and El Mestikawy, S. 1999. Neurotransmitter transporters in the central nervous system. Pharmacol. Rev. 51:439‐464.
   Millan, M.J. 2005. N‐Methyl‐D‐aspartate receptors as a target for improved antipsychotic agents: Novel insights and clinical perspectives. Psychopharmacology (Berl.) 179:30‐53.
   Nagar, B., Bornmann, W.G., Pellicena, P., Schindler, T., Veach, D.R., Miller, W.T., Clarkson, B., Kuriyan, J. 2002. Crystal structures of the kinase domain of c‐Abl in complex with the small molecule inhibitors PD173955 and Imatinib (STI‐571). Cancer Res. 62:4236‐4243.
   Neubig, R.R., Spedding, M., Kenakin, T., and Christopoulos, A. 2003. International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology. Pharmacol. Rev. 55:597‐606.
   Noble, M.E., Endicott, J.A., and Johnson, L.N. 2004. Protein kinase inhibitors: Insights into drug design from structure. Science 303:1800‐1805.
   Obach, R.S., Baxter, J.G., Liston, T.E., Silber, B.M., Jones, B.C., MacIntyre, F., Rance, D.J., and Wastall, P. 1997. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J. Pharmacol. Exp. Ther. 283:46‐58.
   Olivera, B.M., Hillyard, D.R., Marsh, M., and Yoshikami, D. 1995. Combinatorial peptide libraries in drug design: Lessons from venomous cone snails. Trends Biotechnol. 13:422‐426.
   Palm, K., Stenberg, P., Luthman, K., and Artursson, P. 1997. Polar molecular surface properties predict the intestinal absorption of drugs in humans. Pharm. Res. 14:568‐571.
   Petricciani, J.C. 1981. An overview of FDA, IRBs and regulations. IRB 3:1‐3.
   Polli, J.W., Wring, S.A., Humphreys, J.E., Huang, L., Morgan, J.B., Webster, L.O., and Serabjit‐Singh, C.S. 2001. Rational use of in vitro P‐glycoprotein assays in drug discovery. J. Pharmacol. Exp. Ther. 299:620‐628.
   Porsolt, R.D. and Williams, M. 2005. Safety pharmacology. In xPharm (S.J. Enna and D.B. Bylund, executive editors). Elsevier‐MDL, New York.
   http://www.xpharm.com/citation?Article_ID=119961.
   Posner, B.A. 2005. High‐throughput screening‐driven lead discovery: Meeting the challenges of finding new therapeutics. Curr. Opin. Drug Discov. Devel. 8:487‐94.
   Prentis, R.A., Lis, Y., and Walker, S.R. 1988. Pharmaceutical innovation by the seven UK‐owned pharmaceutical companies (1964‐1985). Brit. J. Clin. Pharm. 25:387‐396.
   Pritchard, J.F., Jurima‐Romet, M., Reimer, M.L.J., Mortimer, E., Rolfe, B., and Cayen, N.M. 2003. Making better drugs: Decision gates in non‐clinical drug development. Nature Rev. Drug Discovery 2:542‐553.
   Quitkin, F.M., Rabkin, J.G., Gerald, J., Davis, J.M., and Klein, D.F. 2000. Validity of clinical trials of antidepressants. Am. J. Psychiatry 157:327‐337.
   Repič, O. 1998. Principles of Process Research and Chemical Development in the Pharmaceutical Industry. John Wiley & Sons, New York.
   Riley, R.J. and Grime, K. 2004. Metabolic screening in vitro: Metabolic stability, CYP inhibition and induction. Drug. Disc. Today: Technologies 1:365‐372.
   Roberts, S.A. 2003. Drug metabolism and pharmacokinetics in drug discovery. Curr. Opin. Drug Discov. Devel. 6:66‐80.
   Robertson, J.G. 2005. Mechanistic basis of enzyme‐targeted drugs. Biochemistry 44:5561‐5571.
   Roden, D.M. 2004. Drug‐induced prolongation of the QT interval. N. Engl. J. Med. 350:1013‐1022.
   Sams‐Dodd, F. 2005. Optimizing the discovery organization for innovation. Drug Discov. Today 10:1049‐1056.
   Scarborough, R.M., Laibelman, A.M., Clizbe, L.A., Fretto, L.J., Conley, P.B., Reynolds, E.E., Sedlock, D.M., and Jantzen, H. 2001. Novel tricyclic benzothiazolo[2,3‐c]thiadiazine antagonists of the platelet ADP receptor (P2Y12). Bioorg. Med. Chem. Lett. 11:1805‐1808.
   Schiering, N., Knapp, S., Marconi, M., Flocco, M.M., Cui, J., Perego, R., Rusconi, L., and Cristiani, C. 2003. Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c‐Met and its complex with the microbial alkaloid K‐252a. Proc. Natl. Acad. Sci. U.S.A. 100:12654‐12659.
   Schindler, T., Bornmann, W., Pellicena, P., Miller, W.T., Clarkson, B., and Kuriyan, J. 2000. Structural mechanism for STI‐571 inhibition of Abelson tyrosine kinase. Science 289:1938‐1942.
   Schmid, E.F. and Smith, D.A. 2005. Keynote review: Is declining innovation in the pharmaceutical industry a myth?. Drug Disc Today 10:1031‐1039.
   Sharpe, I.A., Gehrmann, J., Loughnan, M.L., Thomas, L., Adams, D.A., Atkins, A., Palant, E., Craik, D.J., Adams, D.J., Alewood, P.F., and Lewis, R.J. 2001. Two new classes of conopeptides inhibit the alpha1‐adrenoceptor and noradrenaline transporter. Nature Neurosci. 4:902‐907.
   Sneader, W. 1985. Drug Discovery: The Evolution of Modern Medicines. John Wiley & Sons, Chichester, U.K.
   Tang, W., Kang, J., Wu, X., Rampe, D., Wang, L., Shen, H., Li, Z., Dunnington, D., and Garyantes, T. 2001. Development and evaluation of high throughput functional assay methods for HERG potassium channel. J. Biomol. Screen. 6:325‐331.
   Trabanino, R.J., Hall, S.E., Vaidehi, N., Floriano, W.B., Kam, V.W., and Goddard, W.A. 3rd. 2004. First principles predictions of the structure and function of g‐protein‐coupled receptors: Validation for bovine rhodopsin. Biophys. J. 86:1904‐1921.
   van de Waterbeemd, H., Smith, D.A., Beaumont, K., and Walker, D.K. 2001. Property‐based design: Optimization of drug absorption and pharmacokinetics. J. Med. Chem. 44:1313‐1333.
   Van Es, H.H. and Arts, G.J. 2005. Biology calls the targets: Combining RNAi and disease biology. Drug Discov. Today 10:1385‐1391.
   Vassilatis, D.K., Hohmann, J.G., Zeng, H., Li, F., Ranchalis, J.E., Mortrud, M.T., Brown, A., Rodriguez, S.S., Weller, J.R., Wright, A.C., Bergmann, J.E., and Gaitanaris, G.A. 2003. The G‐protein‐coupled receptor repertoires of human and mouse. Proc. Natl. Acad. Sci. U.S.A. 100:4903‐4908.
   Veber, D.F., Johnson, S.R., Cheng, H.Y., Smith, B.R., Ward, K.W., and Kopple, K.D. 2002. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 45:2615‐2623.
   Venter, J.C., Adams, M.D., Myers, E.W., Li, P.W., Mural, R.J., Sutton, G.G. et al. 2001. The sequence of the human genome. Science 291:1304‐1351.
   Vial, C., Roberts, J.A., and Evans, R.J. 2004. Molecular properties of ATP‐gated P2X receptor ion channels. Trends Pharmacol. Sci. 25:487‐493.
   Vieth, M., Siegel, M.G., Higgs, R.E., Watson, I.A., Robertson, D H. Savin, K.A., Durst, G.L., and Hipskind, P.A. 2004. Characteristic physical properties and structural fragments of marketed oral drugs. J. Med. Chem. 47:224‐232.
   Vieth, M., Sutherland, J.J., Roberston, D.H., and Campbell, R.M. 2005. Kinomics: Characterizing the therapeutically validated kinase space. Drug Discov. Today 10:839‐846.
   Wei, Y., Fox, T., Chambers, S.P., Sintchak, J., Coll, J.T., Golec, J.M. Swenson, L., Wilson, K.P., and Charifson, P.S. 2000. The structures of caspases‐1, ‐3, ‐7, ‐8 reveal the basis for substrate and inhibitor selectivity. Chem. Biol. 6:423‐432.
   Wenlock, M.C., Austin, R.P., Barton, P., Davis, A.M., and Leeson, P.D. 2003. A comparison of physiochemical property profiles of development and marketed oral drugs. J. Med. Chem. 46:1250‐1256.
   White, R.E. and Manitpisitkul, P. 2001. Pharmacokinetic theory of cassette dosing in drug discovery screening. Drug Metab. Dispos. 29:957‐966.
   Williams, M. 2003. Target validation. Curr. Opin. Pharmacol. 3:571‐577.
   Williams, M. 2005. Commentary: Systems and integrative biology as alternative guises for pharmacology: Prime time for an iPharm concept?. Biochem Pharmacol. 70:1707‐1716.
   Williams, M. 2006. The genome—5 years on Editorial. Curr. Opin. Invest. Drugs 7:1‐3.
   Yan, Z. and Caldwell, G.W. 2001. Metabolism profiling, and cytochrome P450 inhibition and induction in drug discovery. Curr. Top. Med. Chem. 1:403‐425.
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library