Identification of <i>Plasmodium falciparum</i> apicoplast-targeted tRNA-guanine transglycosylase and its potential inhibitors using comparative genomics, molecular modelling, docking and simulation studies

<div><p>tRNA modifications play an important role in the proper folding of tRNA and thereby determine its functionality as an adaptor molecule. Notwithstanding the centrality of this basic process in translation, a major gap in the genomics of <i>Plasmodium falciparum</i> is unambiguous identification of enzymes catalysing the various tRNA modifications. In this study, tRNA-modifying enzymes of <i>P. falciparum</i> were annotated using homology-based approach. Based on the presence of these identified enzymes, the modifications were compared with those of prokaryotic and eukaryotic organisms. Through sequence comparison and phylogenetic analysis, we have identified <i>P. falciparum</i> apicoplast tRNA-guanine 34 transglycosylase (TGT, EC:, which shows evidence of its prokaryotic origin. The docking analysis of the modelled TGT structures revealed that binding of quinazolinone derivatives is more favourable with <i>P. falciparum</i> apicoplast TGT as compared to human TGT. Molecular dynamic simulation and molecular mechanics/generalized Born surface area analysis of the complex confirmed the greater binding affinity of the ligand in the binding pocket of <i>P. falciparum</i> TGT protein. Further, evolutionary patterning analysis identified the amino acids of <i>P. falciparum</i> apicoplast TGT that are under purifying selection pressure and hence can be good inhibitor-targeting sites. Based on these computational studies, we suggest that <i>P. falciparum</i> apicoplast tRNA-guanine 34 transglycosylase can be a promising drug target.</p></div>