Fragment-based discovery of non-bisphosphonate binders of Trypanosoma brucei farnesyl pyrophosphate synthase.

Fragment-based discovery of non-bisphosphonate binders of Trypanosoma brucei farnesyl pyrophosphate synthase. Chembiochem. 2020 Jun 14;: Authors: Münzker L, Petrick J, Schleberger C, Clavel D, Cornaciu I, Wilcken R, Márquez JA, Klebe G, Marzinzik A, Jahnke W Abstract Trypanosoma brucei (T. brucei) is the causative agent of Human African Trypanosomiasis (HAT). Nitrogen-containing bisphosphonates, a current treatment for bone diseases, have been shown to block the growth of the T. brucei parasites by inhibiting farnesyl pyrophosphate synthase (FPPS); however, due to their poor pharmacokinetic properties they are not well suited for anti-parasitic therapy. Recently, an allosteric binding pocket was discovered on human FPPS, but its existence on trypanosomal FPPS was unclear. Here, we applied NMR and X-ray fragment screening on T. brucei FPPS and report on four fragments bound to this previously unknown allosteric site. Surprisingly, non-bisphosphonate active-site binders were also identified. Moreover, fragment screening revealed a number of additional binding sites. In an early structure-activity relationship (SAR) study, an analogue of an active-site binder was unexpectedly shown to bind to the allosteric site. Overlaying identified fragment binders of a parallel T. cruzi FPPS fragment screen with the T. brucei FPPS structure and medicinal chemistry optimization based on two binders revealed another example of fragment "pocket hoppi...
Source: Chembiochem - Category: Biochemistry Authors: Tags: Chembiochem Source Type: research