RESUMO
Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is the key regulatory enzyme of the purine salvage pathway present in the members of trypanosomatids. The parasite solely depends on this pathway for the synthesis of nucleotides due to the absence of the de novo pathway. This study intends to identify putative inhibitors towards Trypanosoma cruzi HGPRT (TcHGPRT). Initial virtual screening was performed with substructures of phosphoribosyl pyrophosphate (PRPP), an original substrate of HGPRT. Twenty compounds that had greater binding energy than the substrate was treated as hits and was further screened and narrowed down through induced fit docking which resulted in top five compounds which was distinguished into two groups based on the ligand occupancy within the PRPP binding site of TcHGPRT. Group-I compounds (PubChem CID 130316561 and 134978234) are analogous to PRPP structure with greater occupancy, were preferred over Group-II compounds which had lesser occupancy than the substrate. However, one compound (22404820) among Group II was chosen for further analysis considering its significant electrostatic interactions. Molecular docking studies revealed the requirement of an electronegative moiety like phosphate group to be present in the ligand due to the presence of metal ions in the substrate binding site. The three chosen compounds along with PRPP were subjected to molecular dynamics analysis, which indicated a strong presence of electrostatic interaction. Considering the dynamic stability of interactions as well as pharmacological properties of ligands based on absorption, distribution, metabolism, excretion prediction, Group-I compounds were selected as lead compounds and were subjected to molecular electrostatic potential analysis to determine the charge distribution of the compound. The overall analysis thus suggests both 130316561 and 134978234 can be used as TcHGPRT inhibitors. Furthermore, these computational results emphasize the requirement of phosphorylated ligands which are essential in mediating electrostatic interactions and to compete with the binding affinity of the original substrate.
