In this project we aim to project molecules from human metabolic pathways, especially those with enzymes that have been shown to be overexpressed by amastigotes, in chemical property-space defined by ChemGPS-NP. By calculating Euclidian distances between these molecules and molecules from an in-house dataset we can suggest novel inhibitors to metabolic pathways in Leishmania parasites.
As Leishmania parasites are intracellular pathogens, invading human macrophages, effective leishmanicidals must enter the macrophage and then subsequently the parasites. Macrophages expresses several different drug transporters, some of which import drugs (influx pumps) and others that pump out drugs from the cell (efflux pumps) – and these have impact on drug susceptibility of Leishmania parasites. This project will also include projection of molecules that can interact with macrophage drug transporters in chemical property space. Through this we aim to evaluate if these molecules occupies distinct areas in chemical property space – areas occupied by influx pumps are of special interest in the search for new leishmanicidals, whereas areas occupied by efflux pumps should be avoided.
Furthermore, the map of metabolism can be used to predict modes of actions of known leishmanicidals with unknown targets.