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01-10-2013 | SHORT REPORT

In silico analysis of the amido phosphoribosyltransferase inhibition by PY873, PY899 and a derivative of isophthalic acid

Authors: Sidra Batool, Muhammad Sulaman Nawaz, Mohammad A. Kamal

Published in: Investigational New Drugs | Issue 5/2013

Summary

Selectively decreasing the availability of precursors for the de novo biosynthesis of purine nucleotides is a valid approach towards seeking a cure for leukaemia. Nucleotides and deoxynucleotides are required by living cells for syntheses of RNA, DNA, and cofactors such as NADP⁺, FAD⁺, coenzyme A and ATP. Nucleotides contain purine and pyrimidine bases, which can be synthesized through salvage pathway as well. Amido phosphoribosyltransferase (APRT), also known as glutamine phosphoribosylpyrophosphate amidotransferase (GPAT), is an enzyme that in humans is encoded by the PPAT (phosphoribosyl pyrophosphate amidotransferase) gene. APRT catalyzes the first committed step of the de novo pathway using its substrate, phosphoribosyl pyrophosphate (PRPP). As APRT is inhibited by many folate analogues, therefore, in this study we focused on the inhibitory effects of three folate analogues on APRT activity. This is extension of our previous wet lab work to analyze and dissect molecular interaction and inhibition mechanism using molecular modeling and docking tools in the current study. Comparative molecular docking studies were carried out for three diamino folate derivatives employing a model of the human enzyme that was built using the 3D structure of Bacillus subtilis APRT (PDB ID; 1GPH) as the template. Binding orientation of interactome indicates that all compounds having nominal cluster RMSD in same active site’s deep narrow polar fissure. On the basis of comparative conformational analysis, electrostatic interaction, binding free energy and binding orientation of interactome, we support the possibility that these molecules could behave as APRT inhibitors and therefore may block purine de novo biosynthesis. Consequently, we suggest that PY899 is the most active biological compound that would be a more potent inhibitor for APRT inhibition than PY873 and DIA, which also confirms previous wet lab report.

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Title: In silico analysis of the amido phosphoribosyltransferase inhibition by PY873, PY899 and a derivative of isophthalic acid
Authors: Sidra Batool
Muhammad Sulaman Nawaz
Mohammad A. Kamal
Publication date: 01-10-2013
Publisher: Springer US
Published in: Investigational New Drugs / Issue 5/2013
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-013-9944-9

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