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Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results has shown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding not predicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMT inhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting that achieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series with selectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinct series with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain will accelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/non-governmental organisations such as Medical Research Council and Wellcome Trust can stimulate research for neglected diseases.

A method of numerically integrating the Navier-Stokes equations for certain three-dimensional incompressible flows is described. The technique is presented through application to the particular problem of describing thermal convection in a rotating annulus. The equations, in cylindrical polar co-ordinate form, are integrated with respect to time by a marching process, together with the solving of a Poisson equation for the pressure. A suitable form of the finite difference equations gives a computationally-stable long-term integration with reasonably faithful representation of the spatial and temporal characteristics of the flow.Trigonometric interpolation techniques provide accurate (discretely exact) solutions to the Poisson equation. By using an auxiliary algorithm for rapid evaluation of trigonometric transforms, the proportion of computation needed to solve the Poisson equation can be reduced to less than 25% of the total time needed to’ advance one time step. Computing on a UNIVAC 1108 machine, the flow can be advanced one time-step in 2 sec for a 14 × 14 × 14 grid upward to 96 sec for a 60 × 34 × 34 grid.As an example of the method, some features of a solution for steady wave flow in annulus convection are presented. The resemblance of this flow to the classical Eady wave is noted.