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In Silico Analysis of the Amido Phosphoribosyltransferase Inhibition by PY873, PY899 and a Derivative of Isophthalic Acid

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In Silico Analysis of the Amido Phosphoribosyltransferase Inhibition by PY873, PY899 and a Derivative of Isophthalic Acid Invest New Drugs (2013) 31:1355–1363 DOI 10.1007/s10637-013-9944-9 SHORT REPORT In silico analysis of the amido phosphoribosyltransferase inhibition by PY873, PY899 and a derivative of isophthalic acid Sidra Batool & Muhammad Sulaman Nawaz & Mohammad A. Kamal Received: 17 September 2012 /Accepted: 25 February 2013 /Published online: 13 March 2013 # Springer Science+Business Media New York 2013 Summary Selectively decreasing the availability of precursors out for three diamino folate derivatives employing a model of for the de novo biosynthesis of purine nucleotides is a valid the human enzyme that was built using the 3D structure of approach towards seeking a cure for leukaemia. Nucleotides and Bacillus subtilis APRT (PDB ID; 1GPH) as the template. Bind- deoxynucleotides are required by living cells for syntheses of ing orientation of interactome indicates that all compounds RNA, DNA, and cofactors such as NADP+,FAD+, coenzyme A having nominal cluster RMSD in same active site’s deep narrow and ATP. Nucleotides contain purine and pyrimidine bases, polar fissure. On the basis of comparative conformational anal- which can be synthesized through salvage pathway as well. ysis, electrostatic interaction, binding free energy and binding Amido phosphoribosyltransferase (APRT), also known as glu- orientation of interactome, we support the possibility that these tamine phosphoribosylpyrophosphate amidotransferase (GPAT), molecules could behave as APRT inhibitors and therefore may is an enzyme that in humans is encoded by the PPAT block purine de novo biosynthesis. Consequently, we suggest (phosphoribosyl pyrophosphate amidotransferase) gene. APRT that PY899 is the most active biological compound that would catalyzes the first committed step of the de novo pathway using be a more potent inhibitor for APRT inhibition than PY873 and its substrate, phosphoribosyl pyrophosphate (PRPP). As APRT DIA, which also confirms previous wet lab report. is inhibited by many folate analogues, therefore, in this study we focused on the inhibitory effects of three folate analogues on Keywords Amido phosphoribosyltransferase . In silico . APRT activity. This is extension of our previous wet lab work to Inhibition . PY873 . PY899 . Isophthalic acid analyze and dissect molecular interaction and inhibition mech- anism using molecular modeling and docking tools in the cur- Abbreviations rent study. Comparative molecular docking studies were carried APRT Amido phosphoribosyltransferase DIA 5-((4-carboxy-4-(4-(((2,4-diaminopyrido[3,2-d] Electronic supplementary material The online version of this article pyrimidine-6-yl)methyl)amino)benzamido)butyl) (doi:10.1007/s10637-013-9944-9) contains supplementary material, carbamoyl)isophthalic acid which is available to authorized users. DHFR Dihydrofolate reductase M.S.N and S.B have equal contribution for this study. PY899 2,4-diamino-6-(3,4,5-trimethoxybenzyl)-5,6,7,8- S. Batool tetrahydro-quinazoline Functional Informatics Laboratory National Center PY873 2,4-diamino-6-(3,4,5-trimethoxyanilino)- for Bioinformatics, Quaid-I-Azam University, Islamabad, Pakistan methylpyrido[3,2-d]pyrimidine PRPP Phosphoribosyl pyrophosphate M. S. Nawaz Department of BioSciences, COMSATS Institute PRA Phosphoribosylamine of Information Technology, Park Road, Chak Shahzad Islamabad 44000, Pakistan M. A. Kamal (*) Introduction Metabolomics & Enzymology Unit, Fundamental and Applied Biology Group, King Fahd Medical Nucleotides and deoxynucleotides are required by living Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia cells for syntheses of RNA, DNA, and cofactors such as e-mail: [email protected] NADP+,FAD+, coenzyme A and ATP. Inhibition of the 1356 Invest New Drugs (2013) 31:1355–1363 pathways for biosyntheses of nucleotides blocks transcrip- study (wet lab analysis of antifolates) by Kamal and tion and consequently the proliferation of cells. Nucleotides Christopherson [1] which supported that APRT could be contain purine and pyrimidine bases, which can be synthe- inhibited by antifolates. Keeping this in view we performed sized de novo or through salvage pathways. For de novo in-silico study of three potential diamino antifolates inhibitors purine biosynthesis, aspartate, glycine, glutamine, CO2 and to check whether these experimentally verified inhibitors N10-formyltetrahydrofolate are utilized to assemble the pu- could also bind to APRT binding site using molecular docking rine ring of inosine monophosphate (IMP), the first nucleo- technique. We have used human APRT as receptor against tide formed in this pathway [1]. Ribose-phosphate diamino folic acid analogues ligand dataset. As 3D structure diphosphokinase (or phosphoribosyl pyrophosphate synthe- of human APRT is not known till now we have predicted the tase) catalyzes the conversion of ribose-5-phosphate and structure using homology modeling technique and also in- ATP into 5-phosphoribosyl-1-pyrophosphate (PRPP) which cluded the template structure in our docking study against is then transformed into 5-phosphoribosylamine (PRA) by the same ligand dataset. 2,4-Diamino analogues of folic acid the action of amido phosphoribosyltransferase (APRT). have been important in cancer chemotherapy [5]. Although APRT, an enzyme that can be considered as a valid target their biochemical mode of action is complex and not fully for the development of inhibitors that may show anticancer understood, the underlying basis of cell growth inhibition by properties. The APRT is oxygen-sensitive due to an iron- these compounds is their ability to block de novo synthesis of sulfur tetranuclear cluster (4Fe–4S), which shows positive the purine nucleotides, i.e., precursors of DNA. The co-operativity with respect to its substrate PRPP [2], and is polyglutamates of antifolates are pharmacologically important competitively inhibited by adenosine and guanosine and bind tightly to key enzymes of folate metabolism [6]. monophosphates. These monophosphates bind to its catalytic site, where it is subjected to allosteric inhibition by dihydrofolate polyglutamates [4] and a variety of folate ana- Materials and methods logues such as piritrexim (PTX) [4, 5]. On the other hand, its reaction product, PRA, is very labile in nature due to its short 3D Structure prediction half-life (38 s) at 37 °C [3]. For all of the above, specific inhibitors of APRT interacting either via the allosteric site or As the three-dimensional (3D) structure of human APRT is not the catalytic site could have pharmacological use for the available, we used homology modeling for structure predic- treatment of various diseases such as cancer, arthritis, inflam- tion. Homology modeling is a computational procedure that mation and microbial infections. Antifolates and glutamine allows the building of a protein model (for unknown crystal- antagonists which inhibit APRT also inhibit other enzymes lographic structure) using several structural templates (proteins and for this reason have several mechanisms of cytotoxicity. of known structure) [7]. This approach can produce a rational Their metabolic pathway and targeted catalysis has been rep- structural model for any given protein provided there exist resented in Fig. 1. Currently, we have extended our previous related templates having more than 30 % amino acid sequence Fig. 1 Schematic representation of de novo and salvage pathway, cAMP is shown in red color. At this stage inhibition of APRT could where role of ATP, APRT and formyl transferase has been highlighted. be a good target for blocking purine de novo synthesis pathway APRT as catalyzing agent for competitive inhibitor of cGMP and Invest New Drugs (2013) 31:1355–1363 1357 identity [8]. Although a multiple sequence alignment analysis In brief, polar hydrogen atoms and Kollman charges were indicated only 40 % sequence identity between target and assigned to the receptor proteins. For ligands, Gasteiger partial template, none of the active site residues were present in charges were assigned and non-polar hydrogen atoms were Ramachandran’s disallowed region. The RMSD score between merged. All torsions for ligands were allowed to rotate during template and modeled structure was found to be 0.212 Å. docking procedure. The program AutoGrid [20] was used to In order to build a 3D model for human APRT, the 3D generate the grid maps. Each grid was centered at the structure structure of Bacillus subtilis APRT (Protein Data Bank id of the corresponding receptor. The grid dimensions were 1GPH; having resolution 3 Å) was used as the template. The 120×120×120 Å3 with points separated by 0.375 Å. For all Swiss-Model server [9] was used for homology modeling. ligands, random starting positions, random flexible orienta- Swiss Model is a fully automated protein structure homology tions and torsions were used. The translation, quaternion and modeling server accessible via the ExPASy Web server [9]. It torsion steps were taken from default values indicated in takes a sequence alignment and a PDB file as input for the AutoDock4.2 [20]. The Lamarckian genetic algorithm meth- template. These are submitted over a server, and the od was used for minimization using default parameters. The knowledge-based homology model is constructed using the standard docking protocol for rigid and flexible ligand ProModII program [10]. Model construction includes complete docking consisted of 100 runs, using an initial population of backbone and side chain building, loop building, and verifica- 150 randomly placed individuals, with
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