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In Silico Three Dimensional Pharmacophore Models to Aid the Discovery and Design of New Antimalarial Agents

  • Apurba K. Bhattacharjee
  • Mark G. Hartell
  • Daniel A. Nichols
  • Rickey P. Hicks
  • John E. van Hamont
  • Wilbur K. Milhous
Part of the Lecture Notes in Computer Science book series (LNCS, volume 3991)

Abstract

Malaria is one of the most dangerous diseases affecting primarily poor people of tropical and subtropical regions. The search for novel drugs against specific parasites is an important goal for antimalarial drug discovery. This study describes how 3D pharmacophores for antimalarial activity could be developed from known antimalarials and be used as screening tools for virtual compound libraries to identify new antimalarial candidates with examples of indolo[2,1-b]quinazoline-6,12-diones (tryptanthrins) that exhibited in vitro activity below 100 ng/mL. These models mapped on the potent analogues and also onto other well-known antimalarial drugs of different chemical classes including quinolines, chalcones, rhodamine dyes, Pfmrk CDK inhibitors, malarial KASIII inhibitors, and plasmepsin inhibitors. The pharmacophores allowed search and identification of new antimalarials from in-house multi-conformer 3D CIS database and enabled custom designed synthesis of new potent analogues that are found to be potent against in vitro W2, D6, and TM91C235 strains of P. falciparum.

Keywords

Antimalarial Drug Pharmacophore Model Antimalarial Activity Potent Analogue Walter Reed Army Institute 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Malaria Foundation International, http://www.malaria.org/ and sites given therein
  2. Vroman, J.A., Gaston, M.A., Avery, M.A.: Current Progress in the Chemistry, Medicinal Chemistry and Drug Design of Artemisinin Based Antimalarials. Curr. Pharm. Design. 5, 101–138 (1999)Google Scholar
  3. Bhattacharjee, A.K., Karle, J.M.: Stereoelectronic Properties of Antimalarial Artemisinin Analogues in Relation to Neurotoxicity. Chem. Res. Toxicol. 12, 422–428 (1999)CrossRefGoogle Scholar
  4. Bhattacharjee, A.K., Hartell, M.G., Nichols, D.A., Hicks, R.P., Stanton, B., van Hamont, J.E., Milhous, W.K.: Structure-activity relationship study of antimalarial indolo [2,1-b]quinazoline-6-12-diones (tryptanthrins). Three dimensional pharmacophores modeling and identification of new antimalarial candidates. European J. Med. Chem. 39, 59–67 (2004)Google Scholar
  5. Buchwald, P., Bodor, N.: Computer-aided drug design: the role of quantitative structure-property, structure-activity and structure-metabolism relationships (QSPR, QSAR, QSMR). Drug. Future 27, 577–588 (2002)CrossRefGoogle Scholar
  6. Bhattacharjee, A.K., Kyle, D.E., Vennerstrom, J.L., Milhous, W.K.: A 3D QSAR Pharmacophore Model and Quantum Chemical Structure Activity Analysis of Chloroquine(CQ)-Resistance Reversal. J. Chem. Info. Comput. Sci. 42, 1212–1220 (2002)Google Scholar
  7. Bhattacharjee, A.K., Geyer, J.A., Woodard, C.L., Kathcart, A.K., Nichols, D.A., Prigge, S.T., Li, Z., Mott, B.T., Waters, N.C.: A Three Dimensional In Silico Pharmacophore Model for Inhibition of Plasmodium Falciparum Cyclin Dependent Kinases and Discovery of Different Classes of Novel Pfmrk Specific Inhibitors. J. Med. Chem. 47, 5418–5426 (2004)CrossRefGoogle Scholar
  8. CATALYST Version 4.5 software. Accelrys Inc., San Diego, CA (2000)Google Scholar
  9. Slater, A.F.G., Cerami, A.: Inhibition of chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature 355, 167–169 (1992)CrossRefGoogle Scholar
  10. Meshnick, S.R.: In Malaria Parasite Biology, Pathogenesis and Protection: From quinine to qinghaosu: historical perspectives. In: Sherman, I.W. (ed.), pp. 341–353. ASM Press, Washington (1998)Google Scholar
  11. Liu, M., Wilairat, P., Go, M.L.: Antimalarial alkoxylated and hydroxylated chalcones: structure-activity relationship analysis. J. Med. Chem. 44, 4443–4452 (2001)CrossRefGoogle Scholar
  12. Takasu, K., Inoue, H., Kim, H.K., Suzuki, M., Shishido, T., Wataya, Y., Ihara, M.: Rhodacyanine dyes as antimalarials. 1. Preliminary evaluation of their activity and toxicity. J. Med. Chem. 45, 995–998 (2002)CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  • Apurba K. Bhattacharjee
    • 1
  • Mark G. Hartell
    • 1
  • Daniel A. Nichols
    • 1
  • Rickey P. Hicks
    • 1
  • John E. van Hamont
    • 1
  • Wilbur K. Milhous
    • 1
  1. 1.Department of Medicinal Chemistry, Division of Experimental TherapeuticsWalter Reed Army Institute of ResearchSilver SpringU.S.A.

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