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Combinatorial chemistry as a new approach in antiparasitic drug discovery

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Abstract.

Key challenges in antiparasitic drug discovery are target selection and identification of appropriate small molecules as potential ligands for these targets. Novel tools and techniques continue to be developed to address both of these problems. This report focuses on the application of a suite of technologies summarized as combinatorial chemistry. Recent success using these technologies is explored, reasons for frequent failure are given and discussed.

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References

  • Aronov AM, Munagala NR, Kuntz ID, Wang CC (2001) Virtual screening of combinatorial libraries across a gene family: in search of inhibitors of Giardia lamblia guanine phosphoribosyltransferase. Antimicrob Agents Chemother 45:2571–2576

    Google Scholar 

  • Backes BJ, Virgilio AA, Ellman JA (1996) Activation method to prepare a highly reactive acylsulfonamide "safety-catch" linker for solid-phase synthesis. J Am Chem Soc 118:3055–3056

    Google Scholar 

  • Bressi JC, Verlinde CL, Aronov AM, Shaw ML, Shin SS, Nguyen LN, Suresh S, Buckner FS, Van Voorhis WC, Kuntz ID, Hol WG, Gelb MH (2001) Adenosine analogues as selective inhibitors of glyceraldehyde-3-phosphate dehydrogenase of Trypanosomatidae via structure-based drug design. J Med Chem 44:2080–2093

    Google Scholar 

  • Carroll CD, Patel H, Johnson TO, Guo T, Orlowski M, He ZM, Cavallaro CL, Guo J, Oksman A, Gluzman IY, Connelly J, Chelsky D, Goldberg DE, Dolle RE (1998) Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library. Bioorg Med Chem Lett 8:2315–2320

    Google Scholar 

  • Golisade A, Bressi JC, Van Calenbergh S, Gelb MH, Link A (2000) Polymer-assisted solution-phase synthesis of 2′-amido-2′-deoxyadenosine derivatives targeted at the NAD+-binding sites of parasite enzymes. J Comb Chem 2:537–544

    Google Scholar 

  • Golisade A, Herforth C, Quirijnen L, Maes L, Link A (2002) Improving an antitrypanosomal lead applying nucleophilic substitution on a safety catch linker. Bioorg Med Chem 10:159–165

    Google Scholar 

  • Huang L, Lee A, Ellman JA (2002) Identification of potent and selective mechanism-based inhibitors of the cysteine protease cruzain using solid-phase parallel synthesis. J Med Chem 45:676–684

    Google Scholar 

  • Kehoe JW, Maly DJ, Verdugo DE, Armstrong JI, Cook BN, Ouyang YB, Moore KL, Ellman JA, Bertozzi CR (2002) Tyrosylprotein sulfotransferase inhibitors generated by combinatorial target-guided ligand assembly. Bioorg Med Chem Lett 12:329–332

    Google Scholar 

  • Kennedy KJ, Bressi JC, Gelb MH (2001) A disubstituted NAD+ analogue is a nanomolar inhibitor of trypanosomal glyceraldehyde-3-phosphate dehydrogenase. Bioorg Med Chem Lett 11:95–98

    Google Scholar 

  • Lipinski C, Lombardo F, Dominy B, Feeney P (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–25

    Google Scholar 

  • McGovern SL, Caselli E, Grigorieff N, Shoichet BK (2002) A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening. J Med Chem 45:1712–1722

    Google Scholar 

  • Otto S, Furlan RL, Sanders JK (2002) Dynamic combinatorial chemistry. Drug Discov Today 7:117–125

  • Pitcovsky TA, Mucci J, Alvarez P, Leguizamon MS, Burrone O, Alzari PM, Campetella O (2001) Epitope mapping of trans-sialidase from Trypanosoma cruzi reveals the presence of several cross-reactive determinants. Infect Immun 69:1869–1875

    Google Scholar 

  • Reents R, Jeyaraj DA, Waldmann H (2002) Enzymatically cleavable linker groups in polymer-supported synthesis. Drug Discov Today 7:71–76

    Google Scholar 

  • Ring CS, Sun E, McKerrow JH, Lee GK, Rosenthal PJ, Kuntz ID, Cohen FE (1993) Structure-based inhibitor design by using protein models for the development of antiparasitic agents. Proc Natl Acad Sci U S A 90:3583–3587

    Google Scholar 

  • Roche O, Schneider P, Zuegge J, Guba W, Kansy M, Alanine A, Bleicher K, Danel F, Gutknecht EM, Rogers-Evans M, Neidhart W, Stalder H, Dillon M, Sjogren E, Fotouhi N, Gillespie P, Goodnow R, Harris W, Jones P, Taniguchi M, Tsujii S, von der Saal W, Zimmermann G, Schneider G (2002) Development of a virtual screening method for identification of "frequent hitters" in compound libraries. J Med Chem 45:137–142

    Google Scholar 

  • Scharn D, Wenschuh H, Reineke U, Schneider-Mergener J, Germeroth L (2000) Spatially addressed synthesis of amino- and amino-oxy-substituted 1, 3,5-triazine arrays on polymeric membranes. J Comb Chem 2:361–369

    Google Scholar 

  • Smith HK, Bradley M (1999) Comparison of resin and solution screening methodologies in combinatorial chemistry and the identification of a 100 nM inhibitor of trypanothione reductase. J Comb Chem 1:326–332

    Google Scholar 

  • St Hilaire PM, Alves LC, Sanderson SJ, Mottram JC, Juliano MA, Juliano L, Coombs GH, Meldal M (2000) The substrate specificity of a recombinant cysteine protease from Leishmania mexicana: application of a combinatorial peptide library approach. Chembiochem 1:115–122

    Google Scholar 

  • Suresh S, Bressi JC, Kennedy KJ, Verlinde CL, Gelb MH, Hol WG (2001) Conformational changes in Leishmania mexicana glyceraldehyde-3-phosphate dehydrogenase induced by designed inhibitors. J Mol Biol 309:423–435

    Google Scholar 

  • Verlinde CL, Callens M, Van Calenbergh S, Van Aerschot A, Herdewijn P, Hannaert V, Michels PA, Opperdoes FR, Hol WG (1994) Selective inhibition of trypanosomal glyceraldehyde-3-phosphate dehydrogenase by protein structure-based design: toward new drugs for the treatment of sleeping sickness. J Med Chem 37:3605–3613

    Google Scholar 

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Correspondence to Andreas Link.

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Link, A. Combinatorial chemistry as a new approach in antiparasitic drug discovery. Parasitol Res 90 (Suppl 2), S86–S90 (2003). https://doi.org/10.1007/s00436-002-0772-7

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