| DOI | Trouver le DOI : https://doi.org/10.1007/s10822-019-00239-3 |
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| Auteur | Rechercher : Hinge, Vijaya Kumar; Rechercher : Blinov, Nikolay; Rechercher : Roy, Dipankar; Rechercher : Wishart, David S.; Rechercher : Kovalenko, Andriy1 |
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| Affiliation | - Conseil national de recherches du Canada. Nanotechnologie
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| Format | Texte, Article |
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| Sujet | Amyotrophic lateral sclerosis (ALS); Copper zinc superoxide dismutase 1 (SOD1); Solvation free energy; 5-Fluorouridine (5-FUrd); 3D-RISM-KH molecular theory of solvation; W32 binding site |
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| Résumé | Misfolded Cu/Zn superoxide dismutase enzyme (SOD1) shows prion-like propagation in neuronal cells leading to neurotoxic aggregates that are implicated in amyotrophic lateral sclerosis (ALS). Tryptophan-32 (W32) in SOD1 is part of a potential site for templated conversion of wild type SOD1. This W32 binding site is located on a convex, solvent exposed surface of the SOD1 suggesting that hydration effects can play an important role in ligand recognition and binding. A recent X-ray crystal structure has revealed that 5-Fluorouridine (5-FUrd) binds at the W32 binding site and can act as a pharmacophore scaffold for the development of anti-ALS drugs. In this study, a new protocol is developed to account for structural (non-displaceable) water molecules in docking simulations and successfully applied to predict the correct docked conformation binding modes of 5-FUrd at the W32 binding site. The docked configuration is within 0.58 Å (RMSD) of the observed configuration. The docking protocol involved calculating a hydration structure around SOD1 using molecular theory of solvation (3D-RISM-KH, 3D-Reference Interaction Site Model-Kovalenko-Hirata) whereby, non-displaceable water molecules are identified for docking simulations. This protocol was also used to analyze the hydrated structure of the W32 binding site and to explain the role of solvation in ligand recognition and binding to SOD1. Structural water molecules mediate hydrogen bonds between 5-FUrd and the receptor, and create an environment favoring optimal placement of 5-FUrd in the W32 binding site. |
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| Date de publication | 2019-11-04 |
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| Maison d’édition | Springer |
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| Dans | |
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| Langue | anglais |
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| Publications évaluées par des pairs | Oui |
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| Numéro du CNRC | NRC-NANO-44 |
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| Exporter la notice | Exporter en format RIS |
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| Signaler une correction | Signaler une correction (s'ouvre dans un nouvel onglet) |
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| Identificateur de l’enregistrement | c3a56a87-7fee-4cf0-8d43-c354a9cb4b83 |
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| Enregistrement créé | 2020-01-07 |
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| Enregistrement modifié | 2020-03-16 |
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