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In silico Discovery of Chemotherapeutic Agents

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Infectious Disease Informatics

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Abstract

In silico searches of new drug candidates have been considered as a cost-effective alternative to experimental drug screening. The efficiency of in silico approaches relies on important assumptions regarding the target selection, the methods employed, the quality of the drug and target molecule structures, and the computing environment (CPU-limited workstations, grids). The use of in silico methods is sometimes the only possible strategy when the infectious agent cannot be propagated safely or with sufficient reproducibility in a laboratory environment, when the target proteins cannot be heterologously expressed for structural and activity analyses or when the genetic variability requires the specific definition of invariable protein domains as potential targets. When the structure of the target is not available, in silico ligand-based drug design may be the only possible alternative strategy to find novel bioactive molecules. The strengths and limitations of in silico strategies therefore rely on the accuracy of the prior knowledge and assumptions. Here, we focus on Plasmodial proteins as a case study, since these proteins can often not be expressed in recombinant systems and are therefore difficult to characterize structurally using traditional physical approaches. This chapter will (1) briefly address the question of target selection in the context of a parasitic infection such as malaria, (2) introduce the peculiarities of malaria proteins and detail some in silico approaches to describe molecular structures of malaria drug targets, and review subsequent rational approaches for (3) receptor-based and (4) ligand-based drug design. This review also presents the evolution of the computing infrastructures that make in silico experiments possible and particularly discusses the WISDOM initiative for grid-enabled drug discovery against neglected and emergent diseases.

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  1. Institut de Recherches en Technologies et Sciences park le Vivant, CEA Grenoble, France

    Lyn-Marie Birkholtz, Peter Burger, Samia Aci, Hélène Valadié, Ana Lucia da Costa, Loraine Brillet, Tjaart de Beer, Fourie Joubert, Gordon Wells, Vincent Breton, Sylvaine Roy, Abraham Louw & Eric Maréchal

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  1. Sydney Medical School, University of Sydney, Sydney, 2006, Australia

    Vitali Sintchenko

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Birkholtz, LM. et al. (2010). In silico Discovery of Chemotherapeutic Agents. In: Sintchenko, V. (eds) Infectious Disease Informatics. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1327-2_14

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