Insilico structure modeling and molecular docking analysis of phosphoribosyl pyrophosphate amidotransferase (PPAT) with antifolate inhibitors.

Cancer remains the one most serious disease worldwide. Robust metabolism is hallmark of the cancer. PPAT (phosphoribosyl pyrophosphate amidotransferase) catalyzes the first committed step of de novo purine biosynthesis. Hence PPAT, the key regulatory spot in De novo purine nucleotide biosynthesis is an attractive and credible drug target for leukemia and other cancer therapeutics. In the present study detailed computational analysis has been performed for PPAT protein the key enzyme in de novo purine biosynthesis is inhibited by many folate derivatives, hence we aimed to investigate and gauge the inhibitory effect of antifolate derivatives; lomexterol (LTX) methotrexate (LTX), and pipretixin (PTX) with human PPAT to effectively capture and inhibit De novo purine biosynthesis pathway. Sequence to structure computational approaches followed by molecular docking experiments were performed to gain insight into the inhibitory mode, binding orientation and binding affinities of selected antifolate derivatives against important structural features of PPAT. Results indicated strong affinity of antifolate inhibitors for the conserved active site of PPAT molecule encompassing number of hydrophobic, hydrogen bonding, Vander waals and electrostatic interactions. Conclusively, the strong physical interaction of selected antifolate inhibitors with human PPAT suggests the selective inhibition of De novo purine biosynthesis pathway by antifolate derivatives towards cancer therapeutics.