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

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 Plasmodium falciparum is unambiguous identification of enzymes catalysing the various tRNA modifications. In this study, tRNA-modifying enzymes of P. falciparum 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 P. falciparum apicoplast tRNA-guanine 34 transglycosylase (TGT, EC: 2.4.2.29), 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 P. falciparum 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 P. falciparum TGT protein. Further, evolutionary patterning analysis identified the amino acids of P. falciparum apicoplast TGT that are under purifying selection pressure and hence can be good inhibitor-targeting sites. Based on these computational studies, we suggest that P. falciparum apicoplast tRNA-guanine 34 transglycosylase can be a promising drug target.