Structure-based selectivity optimization of piperidine-pteridine derivatives as potent Leishmania pteridine reductase inhibitors.

The upregulation of pteridine reductase (PTR1) is a major contributor to antifolate drug resistance in Leishmania spp., as it provides a salvage pathway that bypasses dihydrofolate reductase (DHFR) inhibition. The structure-based optimization of the PTR1 inhibitor methyl-1-[4-(2,4-diaminopteridin-6-ylmethylamino)benzoyl]piperidine-4-carboxylate (1) led to the synthesis of a focused compound library which showed significantly improved selectivity for the parasite's folate-dependent enzyme. When used in combination with pyrimethamine, a DHFR inhibitor, a synergistic effect was observed for compound 5b. This work represents a step forward in the identification of effective antileishmania agents.

Inhibitor specificity via protein dynamics: insights from the design of antibacterial agents targeted against thymidylate synthase.

Structure-based drug design of species-specific inhibitors generally exploits structural differences in proteins from different organisms. Here, we demonstrate how achieving specificity can be aided by targeting differences in the dynamics of proteins. Thymidylate synthase (TS) is a good target for anticancer agents and a potential target for antibacterial agents. Most inhibitors are folate-analogs that bind at the folate binding site and are not species specific. In contrast, alpha156 is not a folate-analog and is specific for bacterial TS; it has been shown crystallographically to bind in a nonconserved binding site. Docking calculations and crystal structure-based estimation of the essential dynamics of TSs from five different species show that differences in the dynamics of TSs make the active site more accessible to alpha156 in the prokaryotic than in the eukaryotic TSs and thereby enhance the specificity of alpha156.