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.
