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Current Cancer Drug Targets

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

In Silico Structure Modeling and Molecular Docking Analysis of Phosphoribosyl Pyrophosphate Amidotransferase (PPAT) with Antifolate Inhibitors

Author(s): Nousheen Bibi*, Zahida Parveen, Muhammad Sulaman Nawaz and Mohammad Amjad Kamal

Volume 19, Issue 5, 2019

Page: [408 - 416] Pages: 9

DOI: 10.2174/1568009619666181127115015

Price: $65

Abstract

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.

Keywords: Amido phosphoribosyltransferase (PPAT), de novo purine biosynthesis antifolates, molecular docking, cancer therapeutics, robust metabolism, antifolate derivatives.

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[1]
Brayton, K.A.; Chen, Z.; Zhou, G.; Nagy, P.L.; Gavalas, A.; Trent, J.M.; Deaven, L.L.; Dixon, J.E.; Zalkin, H. Two genes for de novo purine nucleotide synthesis on human chromosome 4 are closely linked and divergently transcribed. J. Biol. Chem., 1994, 269(7), 5313-5321.
[2]
Iwahana, H.; Oka, J.; Mizusawa, N.; Kudo, E.; Ii, S.; Yoshimoto, K.; Holmes, E.; Itakura, M. Molecular cloning of human amidophosphoribosyltransferase. Biochem. Biophys. Res. Commun., 1993, 190(1), 192-200.
[3]
Yamaoka, T.; Kondo, M.; Honda, S.; Iwahana, H.; Moritani, M.; Ii, S.; Yoshimoto, K.; Itakura, M. Amidophosphoribosyltransferase limits the rate of cell growth-linked de novo purine biosynthesis in the presence of constant capacity of salvage purine biosynthesis. J. Biol. Chem., 1997, 272(28), 17719-17725.
[4]
Chen, S.; Tomchick, D.R.; Wolle, D.; Hu, P.; Smith, J.L.; Switzer, R.L.; Zalkin, H. Mechanism of the synergistic end-product regulation of Bacillus subtilis glutamine phosphoribosylpyrophosphate amidotransferase by nucleotides. Biochemistry, 1997, 36(35), 10718-10726.
[5]
Chou, K-C. Structural bioinformatics and its impact to biomedical science. Curr. Med. Chem., 2004, 11(16), 2105-2134.
[6]
Cole, C.; Barber, J.D.; Barton, G.J. The Jpred 3 secondary structure prediction server. Nucleic Acids Res, 2008, 36(suppl_2), W197- W201.
[7]
Feldman, R.I.; Taylor, M.W. Purine mutants of mammalian cell lines. II. Identification of a phosphoribosylpyrophosphate amidotransferase-deficient mutant of Chinese hamster lung cells. Biochem. Genet., 1975, 13(3), 227-234.
[8]
Guranowski, A.; Wasternack, C. Adenine and adenosine metabolizing enzymes in cell-free extracts from Euglena gracilis. Comp. Biochem. Physiol. B, 1982, 71(3), 483-488.
[9]
Krahn, J.M.; Kim, J.H.; Burns, M.R.; Parry, R.J.; Zalkin, H.; Smith, J.L. Coupled formation of an amidotransferase interdomain ammonia channel and a phosphoribosyltransferase active site. Biochemistry, 1997, 36(37), 11061-11068.
[10]
McCloskey, D.E.; McGuire, J.; Russell, C.; Rowan, B.; Bertino, J.; Pizzorno, G.; Mini, E. Decreased folylpolyglutamate synthetase activity as a mechanism of methotrexate resistance in CCRF-CEM human leukemia sublines. J. Biol. Chem., 1991, 266(10), 6181-6187.
[11]
Sant, M.; Lyons, S.; Phillips, L.; Christopherson, R. Antifolates induce inhibition of amido phosphoribosyltransferase in leukemia cells. J. Biol. Chem., 1992, 267(16), 11038-11045.
[12]
Gopalakrishnan, K.; Sowmiya, G.; Sheik, S.; Sekar, K. Ramachandran plot on the web (2.0). Protein Pept. Lett., 2007, 14(7), 669-671.
[13]
Laskowski, R.A.; Rullmann, J.A.C.; MacArthur, M.W.; Kaptein, R.; Thornton, J.M. AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J. Biomol. NMR, 1996, 8(4), 477-486.
[14]
Lüthy, R.; Bowie, J.U.; Eisenberg, D. Assessment of protein models with three-dimensional profiles. Nature, 1992, 356, 83-85.
[15]
Flohil, J.; Vriend, G.; Berendsen, H. Completion and refinement of 3‐D homology models with restricted molecular dynamics: Application to targets 47, 58, and 111 in the CASP modeling competition and posterior analysis. Proteins Struct. Funct. Bioinform., 2002, 48(4), 593-604.
[16]
Meng, E.C.; Pettersen, E.F.; Couch, G.S.; Huang, C.C.; Ferrin, T.E. Tools for integrated sequence-structure analysis with UCSF Chimera. BMC Bioinformatics, 2006, 7(1), 339.
[17]
McGuffin, L.J.; Bryson, K.; Jones, D.T. The PSIPRED protein structure prediction server. Bioinformatics, 2000, 16(4), 404-405.
[18]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[19]
Wallace, A.C.; Laskowski, R.A.; Thornton, J.M. LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Protein Eng., 1995, 8(2), 127-134.
[20]
Smith, J.L. Glutamine PRPP amidotransferase: snapshots of an enzyme in action. Curr. Opin. Struct. Biol., 1998, 8(6), 686-694.
[21]
Kupczewska-Dobecka, M. Methotrexate-genotoxic and teratogenic for medical staff of oncology wards? Med. Pr., 2015, 66(2), 265-275.
[22]
Romain, S.; Martin, P.M.; Klijn, J.G.; van Putten, W.L.; Look, M.P.; Guirou, O.; Foekens, J.A. DNA‐synthesis enzyme activity: A biological tool useful for predicting anti‐metabolic drug sensitivity in breast cancer? Int. J. Cancer, 1997, 74(2), 156-161.
[23]
Wang, S-Q.; Du, Q-S.; Huang, R-B.; Zhang, D-W.; Chou, K-C. Insights from investigating the interaction of oseltamivir (Tamiflu) with neuraminidase of the 2009 H1N1 swine flu virus. Biochem. Biophys. Res. Commun., 2009, 386(3), 432-436.

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