Background:
Cancer remains one of the most serious disease worldwide. Robust metabolism
is the hallmark of 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.
Objective:
In the present study, detailed computational analysis has been performed for PPAT protein,
the key enzyme in de novo purine biosynthesis which 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.
Methods:
The sequence to structure computational approaches followed by molecular docking experiments
was performed to gain insight into the inhibitory mode, binding orientation and binding
affinities of selected antifolate derivatives against important structural features of PPAT.
Results: Results indicated a strong affinity of antifolate inhibitors for the conserved active site of
PPAT molecule encompassing a number of hydrophobic, hydrogen bonding, Vander Waals and
electrostatic interactions.
Results:
Results indicated a strong affinity of antifolate inhibitors for the conserved active site of
PPAT molecule encompassing a number of hydrophobic, hydrogen bonding, Vander Waals and
electrostatic interactions.
Conclusion:
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.
The N-atom in [N(PR3)2]+ cations (R = Ph, Me) can act as electron donor for (pseudo) anti-electrostatic interactions
