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Calculation of Free Energy of Binding for Widely Specific Pyrimidine-Nucleoside Phosphorylase and Suspected Inhibitors

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Abstract

Searching for a specific inhibitor of pyrimidine nucleoside phosphorylase (PyNP) was a central objective of the work. The search was carried out by modeling protein–ligand complexes via molecular docking and molecular dynamics (MD), which make it possible to calculate the protein–ligand binding energy ΔGbind. The following compounds were selected as possible inhibitors: 2',3'-didehydro-3'-deoxythymidine (d4T), 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-ioduracil (fiauridine, FIAU), 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-uracil (FAU), and 2-pyrimidin-2-yl-1H-imidazole-4-carboxylic acid (PIA). A preliminary estimate of the binding energy was obtained by the linear interaction energy (LIE) method, and a more accurate calculation was carried out by the free energy perturbation (FEP) method in the GROMACS software package. The calculation results showed that PIA and d4T bind to the active site of Bacillus subtilis PyNP (BsPyNP) with higher affinities as compared with the other putative inhibitors. PIA binds less strongly to human thymidine phosphorylase (hTP). This was assumed to minimize the possible side effects of this compound used for therapeutic purposes.

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ACKNOWLEDGMENTS

The work was carried out using the infrastructure of the High-Throughput Calculations and Big Data Collective Access Center (Informatika Center, Informatics and Management Federal Research Center, Russian Academy of Sciences, Moscow). Regulations of the Informatika Center are available at http://www.frccsc.ru/ckp.

Funding

This work was supported by the Russian Foundation for Basic Research (project no. 19-29-12054, calculations by the FEP method) and the Ministry of Science and Higher Education (state contract with the Crystallography and Photonics Federal Research Center, molecular docking and MD simulations).

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Authors and Affiliations

  1. Shubnikov Institute of Crystallography, Crystallography and Photonics Federal Research Center, Russian Academy of Sciences, 119333, Moscow, Russia

    P. A. Eistrikh-Heller, S. V. Rubinsky, V. R. Samygina & A. A. Lashkov

  2. Kurchatov Institute National Research Center, 123182, Moscow, Russia

    V. R. Samygina

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  1. P. A. Eistrikh-Heller
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  2. S. V. Rubinsky
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  3. V. R. Samygina
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  4. A. A. Lashkov
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Correspondence to P. A. Eistrikh-Heller.

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Translated by T. Tkacheva

Abbreviations: AD, Autodock; BsPyNP, Bacillus subtilis pyrimidine-nucleoside phosphorylase; d4T, 2',3'- didehydro-3'-deoxythymidine; FAU, 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-uracil; FEP, free energy perturbation; FIAU, fiauridine (1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-ioduracil); ΔGbind, protein–ligand binding energy; ΔGcoul, free energy of coupling the Coulomb interaction; ΔGvdw, free energy of coupling the van der Waals interaction defined as the Lennard-Jones potential; ΔΔGDSF, discrete bound finite-size solvent correction; ΔΔGNET, correction for net charge interaction due to periodicity; ΔGrest, restrained binding free energy; ΔΔGRIP, correction for residual integrated potential effects; ΔΔGUSV, correction for under solvation due to periodicity; hTP, human thymidine phosphorylase; LIE, linear interaction energy; MhPyNP, Mycoplasma hyorhinis pyrimidine-nucleoside phosphorylase; PIA, 2-pyrimidin-2-yl-1H-imidazole-4-carboxylic acid; PL, PLANTS; PME, particle mesh Ewald; PyNP, pyrimidine-nucleoside phosphorylase; RMSD, root-mean-square deviation; TI, thermodynamic integration; MD, molecular dynamics

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Eistrikh-Heller, P.A., Rubinsky, S.V., Samygina, V.R. et al. Calculation of Free Energy of Binding for Widely Specific Pyrimidine-Nucleoside Phosphorylase and Suspected Inhibitors. Russ J Bioorg Chem 48, 1262–1272 (2022). https://doi.org/10.1134/S1068162022060103

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