%0 Generic
%A Pöhner, Ina
%C Heidelberg
%D 2020
%F heidok:28399
%R 10.11588/heidok.00028399
%T Computational approaches to drug design against the folate & biopterin pathways of parasites causing neglected tropical diseases
%U https://archiv.ub.uni-heidelberg.de/volltextserver/28399/
%X The neglected tropical diseases leishmaniasis, Chagas disease and African trypanosomiasis, are inflicted by different trypanosomatid parasites and continue to spread. The limited number of available treatment options suffer from side effects and resistance issues, creating a need for novel anti-parasitic medicines. A target pathway of interest for developing anti-trypanosomatidic agents is the folate and biopterin metabolism.  Trypanosomatids are auxotrophs for these metabolites and depend on their reductive activation by dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). However, inhibition of the anti-cancer and anti-bacterial target DHFR failed in trypanosomatids, since PTR1 provides a metabolic bypass of the DHFR activity. Thus, targeting of more than a single protein is required to interfere with the trypanosomatidic folate and biopterin pathway function. PTR1 is unique to the parasites, whereas DHFR has a human homolog representing an important off-target for compound development.  Comparative studies of the sequences, structural data and physicochemical properties of the binding pockets were carried out for PTR1 and DHFR. The computational mapping revealed similarities between the different trypanosomatidic targets and important differences to human off-targets, which were translated into guidelines for the optimization of specific inhibitors of the parasitic target enzymes. Comparative modeling of ten further Leishmania major folate and biopterin pathway proteins expanded the comparison to a near-complete folate pathway pocketome and three biopterin-binding enzyme pockets. From this analysis, further potential off-targets for PTR1-specific inhibitors and additional side targets, for example the methylene tetrahydrofolate reductase or the folylpolyglutamate synthase, were suggested.  Structure-based design and optimization were then carried out based on the target mapping. Building on previously developed thiadiazole-based Leishmania major PTR1 inhibitors, computational docking supported the determination of a structure-activity relationship (SAR) and the design of more effective thiadiazole-based and benzothiazole-based Trypanosoma brucei PTR1 inhibitors. Docking approaches further revealed the SAR for flavonoid inhibitors of different PTR1 variants and allowed for the proposal of core-hopping strategies. Novel pteridine-based inhibitors permitted the combined selective targeting of  PTR1, with picomolar binding affinity, and parasite DHFR. Their design and SAR evaluation was informed by the computational docking predictions and additional efforts to improve the in vitro on-parasite effect on the basis of computationally predicted physicochemical compound descriptors supported the development of compounds with low micromolar in vitro activity against T. brucei bloodstream forms. Computational docking-derived SARs and their use in the design of improved inhibitors were thus successfully coupled with comparative mapping of protein binding pockets and computation-based optimization routines beyond the target level. This computational framework is applicable to the future development of anti-trypanosomatidic agents with different chemical scaffolds.