Mapping metabolic pathways in chemical property space paves the way for new leishmanicidals

Every year 350 million people are at risk of contracting the parasitic disease leishmaniasis [1]. The treatment options for these people are limited to a handful of ineffective expensive drugs associated with severe side effects. Hence, the need for new leishmanicidals is urgent. In this study we present a projection of selected compounds from Leishmania metabolic pathways in a ChemGPS-NP [2] map of chemical property-space. We further demonstrate how this map can be used to search for molecules that can inhibit key enzymes in Leishmania parasites. The parts of this map that cover pathways consisting of enzymes encoded by lateral transferred genes (LGTs) from prokaryote donors, is in focus, as LGTs lack human homologues and are thus potential drug targets [3]. Furthermore, the map of metabolism can be used to predict modes of actions of novel leishmanicidals. This is illustrated in the figure below with representations of the first three dimensions of chemical property space. A is a map of five metabolic pathways (yellow = purine metabolism, blue = pyrimidine metabolism, pink = fructose and mannose metabolism, green = galactose metabolism and purple = glycerophospholipid metabolism). B is the metabolic map overlapped with natural and synthetic compounds, which have activity against Leishmania parasites (grey). A close inspection of B reveals that some leishmanicidals are close to compounds involved in pyrimidine metabolism. These compounds as well as the leishmanicidals are represented in C. Calculating the Euclidian distances between compounds involved in pyrimidine metabolism, and the leishmanicidals reveals that ixoside – a compound isolated from the stem bark of Tecoma mollis [4], is in vicinity of 2'-deoxycytidine diphosphate (dCDP) (D). dCDP is a substrate of nucleoside diphospate kinase (NDK), an enzyme essential for the survival of the parasite inside its host cell [5]. Thus, NDK can be interpreted as a possible drug target for the leishmanicidal compound ixoside.

Keywords: ChemGPS-NP, leishmaniasis, metabolic pathways, drug discovery, prediction.

References:

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