Overview of Chemical Diversity

David J. Triggle1

1 The State University of New York, Buffalo, New York
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 9.1
DOI:  10.1002/0471141755.ph0901s10
Online Posting Date:  May, 2001
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Abstract

In the search for new compounds and the identification of compound sources by the pharmaceutical industry, natural products continue to play an extremely important role, principally because they represent a source, real and potential, of remarkable molecular diversity. Although advances in drug discovery have been significantly fueled and paralleled by advances in synthetic organic chemistry, structural biology, and computational chemistry, they continue to be linked to both natural product and biological chemistry. The dramatic progress in synthetic molecular diversity achieved through combinatorial chemistry is heavily influenced by our understanding of biologically driven molecular diversity. Additionally, through advances in genomics, synthetic chemistry is being linked to biochemical systems to create hybrid “natural‐synthetic“ products, “unnatural“ peptides and “self‐evolving“ molecules. This unit discusses specific instances where diversity is generated by exploitation of biological pathways. These strategies are intimately linked to processes of biological screening, and in particular to high‐throughput screening.

     
 
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Table of Contents

  • High‐Throughput Screening (HTS)
  • Natural Products and the Screening of Biodiversity
  • Modification of Existing Structures
  • Rationally Planned Approaches
  • Identification and Exploitation of Basic Pharmacophores
  • Combinational Chemistry
  • Evolutionary Chemistry
  • Orphan Ligands and Orphan Receptors
  • Literature Cited
  • Figures
     
 
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Materials

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Literature Cited

Literature Cited
   Agarawal, K.C. 1996. Therapeutic actions of garlic constituents. Med. Res. Revs. 16:111‐124.
   Badio, B., Garaffo, H.M., Spande, T.F., and Daly, J.W. 1994. Epibatidine: Discovery and definition as a potent analgesic and nicotinic agonist. Med. Chem. Res. 4:440‐448.
   Balkenhohl, F., van dem Bussche‐Hunnefeld, C., Larsky, A., and Zechel, C. 1996. Combinatorial synthesis of small organic molecules. Angew. Chem. [Ed. Int] 35:2288‐2337.
   Bannon, A.W., Decker, M.W., Holladay, M.W., Curzon, P., Donnelly‐Roberts, D., Puttfarcken, P.S., Bitner, R.S., Diaz, A., Dickenson, A.H., Porsolt, R.D., Williams, M., and Arneric, S.P. 1998. Broadspectrum, non‐opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors. Science 289:77‐80.
   Barker, R. 1996. And the Waters Turned to Blood. Simon and Schuster, New York, N.Y.
   Beaudry, A.A. and Joyce, G.F. 1992. Directed evolution of an RNA enzyme. Science 257:635‐641.
   Bull, A.T., Goodfellow, M., and Slater, J.H. 1992. Biodiversity as a source of innovation in biotechnology. Annu. Rev. Microbiol. 46:219‐252.
   Byers, L.D. and Wolfenden, R. 1973. Binding of the bi‐product analog benzylsuccinic acid by carboxypeptidase A. Biochemistry 12:2070‐2078.
   Chang, R.S.L., 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.
   Cohen, C.J., Spires, S., and van Skiver, D. 1992. Block of T‐type Ca channels in guinea‐pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J. Gen. Physiol. 100:703‐728.
   Cooper, K., Frayk, M.J., Parry, M.H., Richardson, K., and Steele, J. 1992. 1,4‐Dihydropyridines as antagonists of platelet activating factor. I. Synthesis and structure‐activity relationships of 2‐(4‐heterocyclycl)phenyl derivatives. J. Med. Chem. 35:3115‐3129.
   Czarnik, A.W. and Ellman, J.A. (eds.) 1996. Combinatorial Chemistry. Acc. Chem. Res. 29:112‐170.
   Daly, J.W., Garraffo, H.M., and Myers, C.W. 1997. The origin of frog skin alkaloids. Pharmaceutical News 4:9‐14.
   de Vries, D.J. and Hall, M.R. 1994. Marine biodiversity as a source of chemical diversity. Drug Dev. Res. 33:161‐173.
   De‐Zai, D. 1996. Recent advances in Chinese medicine. Drug Dev. Res. 39:123‐200.
   Donevan, S.D., Yamoguchi, S.‐I., and Rogawski, M.A. 1994. Non‐N‐Methyl‐D‐aspartate receptor antagonism by 3‐N‐substituted 2,3‐benzodiazepines: Relationship to anti‐convulsant activity. J. Pharmacol. Exp. Ther. 271:25‐29.
   Evans, B.E., Rittle, K.E., Bock, M.G., DiPardo, R.M., Friedinger, R.M., Whitter, W.L., Lindell, G.F., Veber, D.F., Anderson, P.S., Chang, R.S.L., Lotti, V.J., Cerino, D.J., Chen, T.B., Kling, P.J., Kinkel, K.A., Springer, J.P., and Hirshfield, J. 1988. Methods for drug discovery: Development of potent, selective orally effective cholecystokinin antagonists. J. Med. Chem. 31:2235‐2246.
   Flam, F. 1994. Co‐opting a blind watchmaker. Science 265:1032‐1033.
   Furukawa, T., Aukida, T., Suzuki, K., Fujita, Y., Mori, Y., Nishimura, M., and Yamanaka, M. 1997. Voltage and pH dependent block of cloned N‐type Ca2+ channels by amlodipine. Brit. J. Pharmacol. 121:1136‐1140.
   Goldmann, S. and Stoltefuss, J. 1991. 1‐4‐Dihydropyridines: Effect of chirality and conformation on the calcium antagonist and agonist activities. Angew. Chemie Int. Ed. English 30:1559‐1578.
   Gotoh, Y. Imazumi, Y., Watanabe, M., Shibata, E.F., Clark, R.B., and Giles, W.R. 1991. Inhibition of transient outward K+ current by DHP Ca2+ antagonists and agonists in rabbit cardiac myocytes. Am. J. Physiol. 260:H1737‐H1742.
   Greer, J., Erickson, J.W., Baldwin, J.J., and Varney, M.D. 1994. Application of the three‐dimensional structures of protein target molecules in structure‐based drug design. J. Med. Chem. 37:1037‐1054.
   Hopf, F.W., Reddy, P., Hong, J., and Steinhardt, R.A. 1996. A capacitative calcium current in cultured skeletal muscle cells is mediated by the calcium‐specific leak channel and inhibited by dihydropyridine compounds. J. Biol. Chem. 271:22358‐22367.
   Jacobsen, J.R., Hutchinson, C.R., Cane, D.E., and Khosla, C. 1997. Precursor‐directed biosynthesis of erythromycin analogs by an engineered polyketide synthase. Science 277:367‐369.
   Johnson, R.E., Baizman, E.R., Becker, C., Bohnet, E.A. et al. 1993. 4,5‐Dihydro‐1‐phenyl‐lH‐2,4‐benzodiazepines: Novel antiarrhythmic agents. J. Med. Chem. 36:3361‐3370.
   Kellar, K.J. 1995. Epibatidine:Its pharmacologic actions and utility for studying neuronal nicotinic receptors. Neurotransmissions XI, November, 1995, Research Biochemicals, Natick, Mass.
   Kessler, H. 1997. Structure‐activity relationship by NMR. A new procedure for drug discovery by a combinatorial‐rational approach. Angew. Chem. Int. Ed. English 30:829‐831.
   Khosla, C. and Zawada, R.J.X. 1996. Generation of polyketide libraries via combinatorial biosynthesis. Trends Biotechnol. 14:137‐142.
   Kingston, D.G.L. 1996. Natural products as pharmaceuticals and sources for lead studies. In The Practice of Medicinal Chemistry (C.G. Wermuth, ed.) pp. 100‐116. Academic Press, London.
   Lesburg, C.A., Zhai, G., Cone, D.E., and Christianson, D.W. 1997. Crystal structure of pentalenene synthase: Mechanistic insights on terpenoid cyclization reactions in biology. Science 277:1820‐1824.
   Li, S.‐N., Brater, M., and Andrews, K. 1997. Nimodipine and nitrendipine inhibit N‐type Ca2+ channels in dibutyryl cAMP‐differentiated neuroblastoma and gloma hybrid (NG l08‐l5) cells. Neurosci. Lett. 230:85‐88.
   Linde, K., Ramirez, G., Mulrow, C.D., Pauls, A., Weidenhammer, W., and Melchart, D. 1996. St. John's wort for depression—An overview and meta‐analysis of randomized clinical trials. Br. Med. J. 313:253‐258.
   Meunier, J.‐C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., Butour, J.L., Guilemot, J.‐C., Ferrara, C., Monsarrat, B., Mazarguil, H., Vassart, G., Costentin, J. 1995. Isolation and structure of the endogenous agonist of the opioid receptor‐lke ORL1 receptor. Nature 377:532‐535.
   Mitscher, L.A., Jung, M., Shankel, D., Dow, J.‐H., Steele, L., and Pillai, S.M. 1997. Chemoprotection: A review of the potential therapeutic antioxidant properties of green tea (Canelia sinensis) and certain of its constituents. Med. Res. Rev. 17:327‐366.
   Miyawaki, H., Yamazaki, F., Furuta, T. Shigei, T., and Yamauchi, H. 199l. Antiarrhythmic effects of a novel Na+ and Ca2+ channel blocker, SD‐32l3. A comparison with its enantiomer. Drug Dev. Res. 22:293‐298.
   Mollereau, C., Parmentier, M., Mailleux, P., Butour, J.L., Moisand, C., Chalon, P., Caput, D., Vassart, C., Meunier, J.C. 1994. ORLI, a novel member of the opioid receptor family. FEBS Lett. 341:33‐38.
   Olivera, B.M., Miljanich, G., Ramachardran, J., and Adams, M.E. 1994. Calcium channel diversity and neurotransmitter release. Annu. Rev. Biochem. 63:823‐867.
   Olivera, B.M., Hillyard, D.R., Marsh, M., and Yoshikami, D. 1995. Combinatorial peptide libraries in drug design: Leads from venomous cone snakes. Trends Biotechnol. 13:422‐426.
   Ondetti, M.A. 1994. From peptides to peptidases:A chronicle of drug discovery. Ann. Rev. Pharmacol. Toxicol. 34:1‐16.
   Papaageorgiou, C. and Borer, X. 1996. A non‐peptide ligand for the somatostatin receptor having a benzodiazepine structure. Bioorg. Med. Chem. Lett. 6:267‐272.
   Plotkin, M.J. 1993. Tales of a Shaman's Apprentice, Viking Press, New York, NY.
   Repke, K.R.H. 1997. Toward the discovery of digitalis derivatives with inotropic selectivity. Drug Discovery Today 2:110‐116.
   Riddle, J.M. and Estes, J.W. 1992. Oral contraceptives in ancient and medieval times. Am. Sci. 80:226‐234.
   Romer, D., Buscher, H.H., Hill, R.C., Maurer, R., Petcher, T.J., Zeugner, H., Benson, W., Finner, E., Milkowski, W., and Thies, P.W. 1982a. An opioid benzodiazepine. Nature 298:759‐760.
   Romer, D., Buscher, H.H., Hill, R.C., Maurer, R., Petcher, T.J., Zeugner, H., Benson, W., Finner, E., Milkowski, W., and Thies, P.W. 1982b. Unexpected opioid activity in a known class of drug. Life Sci. 31:1217‐1330.
   Sacchettini, J.C. and Poulter, C.D. 1997. Creating isoprenoid diversity. Science 277:1788‐1789.
   Service, R.F. 1997. Hijacking a cell's chemical paths to make new antibiotics. Science 277:319.
   Shuker, S.B., Hajduk, P.J., Meadows, R.P., and Fesik, S.W. 1996. Discovering high‐affinity ligands for proteins: SAR by NMR. Science 274:1531‐1534.
   Sternbach, L.H. 1979. The benzodiazepine story. J. Med. Chem. 22:1‐7.
   Stout, D.M. and Meyers, A.I. 1982. Recent advances in the chemistry of 1,4‐dihydropyridines. Chem. Rev. 82:223‐242.
   Triggle, D.J. 1992. Calcium‐channel antagonists: Mechanisms of action, vascular selectivities and clinical relevance. Clevel. Clin. J. Med. 59:617‐627.
   Triggle, D.J. 1997. Mechanisms of action of calcium channel antagonists. In Calcium Antagonists in Clinical Medicine. 2nd edition (M. Epstein, ed.) pp. 1‐26. Hanley & Belfus, Philadelphia.
   Trivedi, S., Potter‐Lee, L., McConville, M.W., Li, J.H., Ohnmacht, C.J., Trainor, D.A., and Kau, S.T. 1995. K‐channel opening activity of dihydropyridine ZM244085 effect on 86Rb efflux and 3H‐P1075 binding in urinary bladder smooth muscle. Res. Commun. Mol. Path. Pharmacol. 88:137‐151.
   Turek, C., and Gold, L. 1990. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249:505‐510.
   vanRhee, A.M., Wiang, J.‐L., Melman, N., Olah, M.E., Stiles, G.L., and Jacobson, K.A. 1996. Interaction of 1,4‐dihydropyridine and pyridine derivatives with adenosine receptors selectivity for A3 receptors. J. Med. Chem. 39:2980‐2989.
   Wetzel, J.M., Miao, S.W., Forray, C., Borden, L.A., Branchek, T.A., and Gluchowski, C. 1995. Discovery of (1a‐adrenergic receptor antagonists based on the L‐type Ca2+ channel antagonist niguldipine. J. Med. Chem. 38:1579‐1581.
   Wexler, R.R., Greenlee, W.J., Irvin, J.D., Goldberg, M.R., Prendergast, K., Smith, R.D., Timmermans, P.B.M.W.M. 1996. Nonpeptide angiotensin II receptor antagonists. The next generation in antihypertensive therapy. J. Mol. Chem. 39:625‐656.
   Whittle, P.J. and Blondell, T.L. 1994. Protein structure‐based drug design. Ann. Rev. Biophys. Biomol. Struct. 23:349‐375.
   Wiley, R.A. and Rich, D. 1993. Peptidomimetics derived from natural products. Med. Res. Rev. 13:327‐384.
   Zhang, X., Anderson, J.W., and Fedida, D. 1997. Characterization of nifedipine block of the human heart delayed rectifier hKVl.5. J. Pharmacol. Exp. Ther. 281:1247‐1256.
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