[Contemporary strategies and methods of modeling antiparasitic drugs]

Contemporary methods of directed chemotherapy are based on multi-step procedures, which require co-ordinated activities of interdisciplinary teams of biochemists, pharmacologists, geneticists, crystallographers as well as computer scientists. Biochemists select the proper target, such as an enzyme, throughout screening of the biochemical influence of compounds-potential drugs on this target. For further research they use targets with very low inhibition constants (> 10(-6) M). Determination of the relation between therapeutic activity of the compound and modelling of its chemical structure constitutes an important part of the procedure. The most important part of the procedure is the recognition of the primary structure of the target. The two following pathways allow to do that: 1. isolation of DNA and gDNA or cDNA-started cloning of a gene responsible for production of the target protein and then its sequencing. 2. purification and crystallization of the target protein and further computer-aided processing of crystallographic data in order to determine the primary structure. Computational chemistry (C/C) methods are the basic part of the procedure of molecular modelling (M/M) of a target molecule and its interactions with a molecule of the future drug. Data obtained using a technology which engages the C/C and M/M methods not only allow to determine the aminoacid sequence of the target protein in question (e.g. a unique parasite enzyme); they also enable to further speculate on its secondary and tertiary structures. Such structure includes specified number of repeated motifs of alpha-helixes, beta-sheets and loops or turns. Particularly, the "barrel" structure is very common in numerous enzymes. Two following examples of research on target-antiparasitic drug interactions is presented. They are the interaction between phosphoglicerate kinase in Leishmania and drug suramin and malic enzyme of Trichinella and drug closantel. New promising targets for new anti-protozoan drugs (protozoa of Trypanosoma species) include e.g. microbody translocation signal in kinetosom proteins (SKL) or protein blocking the transport of proteins to glycosomes-metabolic centres in Trypanosoma (repetitive groups of QRLQ). Recently, scientists from Arris Pharmaceutical (San Francisco) have considered, employing new data, up to 100 to fully characterize the surface structure of a molecule, using the systems of artificial intelligence.