Nousheen Bibi*, Zahida Parveen, Muhammad Sulaman Nawaz and Mohammad Amjad KamalPages 408-416 (9)
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.
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.
Amido phosphoribosyltransferase (PPAT), de novo purine biosynthesis antifolates, molecular docking, cancer therapeutics, robust metabolism, antifolate derivatives.
Department of Bioinformatics, Shaheed Benazir Bhutto Women University Peshawar, Peshawar, KPK, Department of Biological Sciences, Quaid-i-Azam University, Islamabad, Department of BioSciences, COMSATS Institute of Information Technology, Park Road, Chak Shahzad Islamabad-44000, King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589