Structural considerations for designing adenosine analogs as selective inhibitors of Trichomonas sp. glyceraldehyde-3- phosphate dehydrogenase.

Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of pathogenic protozoa Trichomonas vaginalis (TvGAPDH) is an attractive drug target since this parasite lacks functional citric acid cycle and is dependent solely on glycolysis for its energy requirements. The three dimensional structure of TvGAPDH dimer has been generated by homology modelling based on the crystal structure of human liver GAPDH. Comparison of the NAD;{+} binding pocket of the modeled TvGAPDH with human GAPDH (hGAPDH) reveals the presence of a hydrophobic pocket near the N-6 position of adenine ring as well as a hydrophobic cleft near O-2' of the adenosine ribose that are absent in the human enzyme. In order to exploit these structural differences adenosine and several adenosine analogs with substitution on N-6 position of adenine ring or 2' position of ribose sugar or both have been studied by docking experiments using the program AutoDock version 3.0.5. Our docking result suggests that bulkier hydrophobic substitution at the N-6 position of the adenine ring could form more stable complexes with TvGAPDH than with hGAPDH. An improvement of binding occurs in TvGAPDH when methoxybenzamido group has been introduced at the O-2' position of the ribose sugar. The combination of N-6 and O-2' substitutions may have produced significantly improved inhibitors. Our study may help in identifying structural elements involved in the origin of selectivity at the NAD;{+} binding pocket of TvGAPDH. This study could further be extended for future anti-trichomonal drug design strategies in order to control trichomoniasis.