Abstract.
The discovery and optimization of antiparasitic compounds has profited by information-based methods newly emerged in the modern drug development process. The generation of computer models enables the cost-efficient and fast computational screening of virtual compound libraries for biologically active molecules. Two sources of information are available: structure-based drug design utilizes information about the disease target. We describe two different computational approaches, realized as the fast, flexible docking program FlexX and as the de novo design program LUDI. Ligand-based drug design, on the other hand, requires the structures and experimental data from biologically active compounds. Parasitic targets and antiparasitic compounds studied by various information-based methods include trypanosomal trypanothione reductase, antiprotozoal bisphosphonates, and trypanosomal glycosomal glyceraldehyde-3-phosphate dehydrogenase.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Allen FH, Kennard O (1993) 3D search and research using the Cambridge structural database. Chem Des Auto News 8:130–137
Aronov AM, Verlinde CLMJ, Hol WGJ, Gelb MH (1998) Selective tight binding inhibitors of trypanosomal glyceraldehyde-3-phosphate dehydrogenase via structure based design. J Med Chem 41:4790–4799
Aronov AM, Suresh S, Buckner FS, Van Voorhis WC, Verlinde CLMJ, Opperdoes FR, Hol, WGJ, Gelb, MH (1999) Structure-based design of submicromolar, biological active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci U S A 96:4273–4278
Avery MA, Alvim-Gaston M, Rodrigues CR, Barreiro EJ, Cohen FE, Sabnis YA, Woolfrey JR (2002) Structure-activity relationships of the antimalarial agent artemisinine. 6. The development of predictive in vitro potency models using CoMFA and HQSAR methodologies. 45:292–303
Böhm HJ (1992) LUDI: a new method for the de novo design of enzyme inhibitors. J Comput Aided Mol Des 6:61–78
Bond CS, Zhang Y, Berriman M, Cunningham ML, Fairlamb AH, Hunter WN (1999) Crystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione and the structure based discovery of new natural product inhibitors. Structure 7:81–89
Bressi JC, Verlinde CLMJ, Aronov AM, Shaw ML, Shin SS, Nguyen LN, Suresh S, Buckner FS, Van Voorhis WC, Kuntz ID, Hol WGJ, 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
Cramer RD, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (CoMFA) 1. Effect of shape on binding of steroids on carrier proteins. J Am Chem Soc 110:5959–5967
Hansch C, Fujita T (1964) A method for the correlation on biological activity and chemical structure. J Am Chem Soc 86:1616–1626
Jacoby EM, Schlichting I, Lantwin CB, Kabsch W, Krauth-Siegel RL (1996) Crystal structure of the Trypanosoma cruzi trypanothione reductase-mepacrine complex. Proteins 24:73–80
Jones G, Wilett P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267:727–748
Klebe G (1998) Comparative molecular similarity indices analysis: CoMSIA. Perspect Drug Discov Des 12: 87–104
Kramer B, Metz G, Rarey M, Lengauer T (1999) Ligand docking and screening with FlexX. Med Chem Res 9:463–478
Krieger S, Schwarz W, Ariyanayagam MR, Fairlamb AH, Krauth-Siegel RL, Clayton C (2000) Trypanosomes lacking trypanothione reductase are avirulent and show increased sensitivity to oxidative stress. Mol Microbiol 35:542–552
Kuntz ID, Blanly JM, Oatley SJ, Langridge R, Ferrin TEA (1982) A geometric approach to macromolecule ligand interactions. J Mol Biol 161:269–288
Li R, Chen X, Gong B, Selzer PM, Li Z, Davidson E, Kurzban G, Miller RE, Nuzum EO, McKerrow JH, Fletterick RJ, Gillmor SA, Craik CS, Kuntz ID, Cohen FE, Kenyon, GL (1996) Structure-based design of parasitic protease inhibitors. Bioorg Med Chem Lett 4:1421–1427
Martin MB, Grimley JS, Lewis JC, Heath HT, Bailey BN, Kendrick H, Yardley V, Caldera A, Lira R, Urbina JA, Moreno SN, Docampo R, Croft SL, Oldfield E (2001) Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii and Plasmodium falciparum: a potential route to chemotherapy. J Med Chem 44:909–916
Martin MB, Sanders JM, Kendrick H, de Luca-Fradley K, Lewis JC, Grimley JS, van Brussel EM, Olsen JR, Meints GA; Burzynska A, Kafarski P, Croft SL, Oldfield E (2002) Activity of bisphosphonates against Trypanosoma brucei rhodesiense. J Med Chem 45:2904–2914
Morris GM, Goodsell DS, Halliday Huey R, Hart W, Belew RK, Olson AJ (1998) Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662
Rarey M, Kramer B, Lengauer T, Klebe G (1996) A fast flexible docking method using an incremental construction algorithm. J Mol Biol 261:470–489
Rarey M, Kramer B, Lengauer T (1997) Protein-ligand docking based on incremental construction without manual intervention. J Comput Aided Mol Des 11:369–384
Rodan GA, Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289:1508–1514
Rodigues CR, Flaherty TM, Springer C, McKerrow JH, Cohen FE (2002) CoMFA and HQSAR of acylhydrazide cruzain inhibitors. Bioorg Med Chem Lett 12:1537–1541
Schneider G, Böhm H-J (2002) Virtual screening and fast automated docking methods. Drug Discov Today 7:64–70
Walters WP, Stahl MT, Murcko MA (1998) Virtual screening – an overview. Drug Discov Today 3:160–178
Xu D, Xu Y, Uberbacher EC (2000) Computational tools for protein modeling. Curr Protein Pept Sci 1: 1–21
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wolf, K., Dormeyer, M. Information-based methods in the development of antiparasitic drugs. Parasitol Res 90 (Suppl 2), S91–S96 (2003). https://doi.org/10.1007/s00436-002-0773-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-002-0773-6