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Abstract

In bacterial and archaeal purine biosynthetic pathways, sixth step involves utilization of enzyme PurE, catalyzing the translation of aminoimidazole ribonucleotide to 4-carboxy-5-aminoimidazole ribonucleotide (CAIR) with carbon dioxide. The formation of CAIR takes place through an unstable intermediate N5-CAIR, played by two enzymes—N5-CAIR synthetase (PurK) and N5-CAIR mutase (PurE) that further catalyzes the reaction of N5-CAIR to CAIR. In this study, N5-CAIR mutase (PH0320) from Pyrococcus horikoshii OT3 (PurE) was considered. The three-dimensional structure of Pyrococcus horikoshii OT3 was modeled based on the structure of PurE from Escherichia coli. The modeled structure was subjected to molecular dynamics simulation up to 100 ns, and least energy structure from the simulation was subjected to virtual screening and induced fit docking to identify the best potent leads. A total of five best antagonists were identified based on their affinity and mode of binding leading with conserved residues Ser18, Ser20, Asp21, Ser45, Ala46, His47, Arg48, Ala72, Gly73, Ala75, and His77 promotes the activity of Ph-N5-CAIR mutase. In addition to molecular dynamics, absorption, digestion, metabolism, and excretion properties, binding free energy and density functional theory calculations of compounds were carried out. Based on analyses, compound from National Cancer Institute (NCI) database, NCI_826 was adjudged as the best potent lead molecule and could be suggested as the suitable inhibitor of N5-CAIR mutase.

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References

Binkley

J.S.

, Pople

J.A.

, and Hehre

W.J.

1980. Self-consistent molecular orbital methods. 21. Small split-valence basis sets for first row elements. J. Am. Chem. Soc. 102, 939–947.

Colovos

, and Yeates

T.O.

1993. Verification of protein structures: Patterns of non-bonded atomic interactions. Protein. Sci. 2, 1511–1519.

Constantine

C.Z.

, Starks

C.M.

, Mill

C.P.

, et al. 2006. Biochemical and structural studies of N5-carboxyaminoimidazole ribonucleotide mutase from the acidophilic bacterium Acetobacter aceti. Biochemistry. 45, 8193–8208.

Daga

P.R.

, and Doerksen

R.J.

2008. Stereoelectronic properties of spiroquinazolinones in differential PDE7 inhibitory activity. J. Comput. Chem. 29, 1945–1954.

Dagan-Wiener

, et al. 2017. Bitter or not? BitterPredict, a tool for predicting taste from chemical structure. Scientific Reports. Vol. 7, article #12074.

Dehez

, Pebay-Peyroula

, and Chipot

2008. Binding of ADP in the mitochondrial ADP/ATP carrier is driven by an electrostatic funnel. J. Am. Chem. Soc. 130, 12725–12733.

Eswar

, Eramian

, Webb

, et al. 2008. Protein structure modeling with MODELLER. Methods. Mol. Biol. 426, 145–159.

Firestine

S.M.

, Paritala

, McDonnell

J.E.

, et al. 2009. Identification of inhibitors of N5-carboxyaminoimidazole ribonucleotide synthetase by high-throughput screening. Bioorg. Med. Chem. 17, 3317–3323.

Friesner

R.A.

, Murphy

R.B.

, Repasky

M.P.

, et al. 2006. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem. 49, 6177–6196.

10.

Guru Raj Rao

, Biswal

, Prabhu

, et al. 2016. Identification of potential inhibitors for AIRS from de novo purine biosynthesis pathway through molecular modeling studies—A computational approach. J. Biomol. Struct. Dyn. 34, 2199–2213.

11.

Halgren

T.A.

, Murphy

R.B.

, Friesner

R.A.

, et al. 2004. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem. 47, 1750–1759.

12.

Hess

, Bekker

, Berendsen

H.J.C.

et al., 1997. LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem. 18, 1463–1472.

13.

Kappock

T.J.

, Ealick

S.E.

, and Stubbe

2000. Modular evolution of the purine biosynthetic pathway. Curr. Opin. Chem. Biol. 4, 567–572.

14.

Kenny

P.W.

2009. Hydrogen bonding, electrostatic potential, and molecular design. J. Chem. Inf. Model. 49, 1234–1244.

15.

Laskowski

R.A.

, MacArthur

M.W.

, Moss

D.S.

, et al. 1993. Procheck: A program to check the stereochemical quality of protein structures. J. Appl. Cryst. 26, 283–291.

16.

S.X.

, Tong

Y.P.

, Xie

X.C.

, et al. 2007. Octameric structure of the human bifunctional enzyme PAICS in purine biosynthesis. J. Mol. Biol. 366, 1603–1614.

17.

Mathews

I.I.

, Kappock

T.J.

, Stubbe

, et al. 1999. Crystal structure of Escherichia coli PurE, an unusual mutase in the purine biosynthetic pathway. Structure. 7, 1395–1406.

18.

McFarland

W.C.

, and Stocker

B.A.D.

1987. Effect of different purine auxotrophic mutations on mouse-virulence of a Vi-positive strain of Salmonella Dublin and of two strains of Salmonella Typhimurium. Microb. Pathog. 3, 129–141.

19.

Meyer

, Leonard

N.J.

, Bhat

, et al. 1992. Purification and characterization of the purE, purK, and purC gene products: Identification of a previously unrecognized energy requirement in the purine biosynthetic pathway. Biochemistry. 31, 5022–5032.

20.

Mueller

E.J.

, Meyer

, Rudolph

, et al. 1994. N5-carboxyaminoimidazole ribonucleotide: Evidence for a new intermediate and two new enzymatic activities in the de novo purine biosynthetic pathway of Escherichia coli. Biochemistry. 33, 2269–2278.

21.

Murray

A.W.

1971. The biological significance of purine salvage. Annu. Rev. Biochem. 40, 811–826.

22.

Nam

, Gao

J.L.

, and York

D.M.

2008. Electrostatic interactions in the hairpin ribozyme account for the majority of the rate acceleration without chemical participation by nucleobases. RNA. 14, 1501–1507.

23.

Robert

, and Gouet

2014. Deciphering key features in protein structures with the new ENDscript server. Nucleic. Acids Res. 42, 320–324.

24.

Sastry

G.M.

, Adzhigirey

, Day

, et al. 2013. Protein and ligand preparation Parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aid. Mol. Des. 27, 221–234.

25.

Schrödinger Release. 2018. Maestro, LLC. New York NY.

26.

Schüttelkopf

A.W.

, and Van Aalten

D.M.

2004. PRODRG: A tool for high-throughput crystallography of protein-ligand complexes. Acta. Crystallogr. D Biol. Crystallogr. 60, 1355–1363.

27.

Sherman

, Day

, Jacobson

M.P.

, et al. 2006. Novel procedure for modeling ligand/receptor induced fit effects. J. Med. Chem. 49, 534–553.

28.

Singh

K.D.

, Kirubakaran

, Nagarajan

, et al. 2011. Homology modeling, molecular dynamics, e-pharmacophore mapping and docking study of chikungunya virus nsP2 protease. J. Mol. Model. 18, 39–51.

29.

Thompson

J.D.

, Higgins

D.G.

, and Gibson

T.J.

1994. CLUSTALW: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic. Acids Res. 22, 4673–4680.

30.

Tranchimand

, Starks

C.M.

, Mathews

I.I.

, et al. 2011. Treponema denticola PurE is a bacterial AIR carboxylase. Biochemistry. 50, 4623–4637.

31.

Van Der Spoel

, Lindahl

, Hess

, et al. 2005. GROMACS: Fast, flexible, and free. J. Comput. Chem. 26, 1701–1718.

32.

Watanabe

, Sampei

, Aiba

, et al. 1989. Identification and sequence analysis of Escherichia coli purE and purK genes encoding 5′-phosphoribosyl-5-amino-4 imidazole carboxylase for de novo purine biosynthesis. J. Bacteriol. 171, 198–204.

33.

Wiederstein

, and Sippl

2007. ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic. Acids Res. 35, 407–410.

34.

Wolan

D.W.

, Cheong

C.G.

, Greasley

S.E.

, et al. 2004. Structural insights into the human and avian IMP cyclohydrolase mechanism via crystal structures with the bound XMP inhibitor. Biochemistry. 43, 1171–1183.

35.

Zhang

, Morar

, and Ealick

S.E.

2008. Structural biology of the purine biosynthetic pathway. Cell. Mol. Life Sci. 65, 3699–3724.

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Exploration of N5-CAIR Mutase Novel Inhibitors from Pyrococcus horikoshii OT3: A Computational Study

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