Journal of Computer-Aided Molecular Design

, Volume 33, Issue 10, pp 913–926 | Cite as

The role of hydration effects in 5-fluorouridine binding to SOD1: insight from a new 3D-RISM-KH based protocol for including structural water in docking simulations

  • Vijaya Kumar Hinge
  • Nikolay Blinov
  • Dipankar Roy
  • David S. Wishart
  • Andriy KovalenkoEmail author


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.


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 



This work was supported by funding from the Alberta Innovates, Alberta Prion Research Institute (Research Team II Program ABIBS APRIRTP 201300023 and Explorations V Program ABIBS APRIEP 201600034). VKH, NB, DR and AK acknowledge our industrial collaborator, Chemical Computing Group (CCG), for generous access to the Molecular Operating Environment (MOE) drug discovery software platform. Computational resources were provided by WestGrid ( and Compute Canada - Calcul Canada ( We thank Dr. Carol Ladner-Keay for help in editing the manuscript. The manuscript was written through contributions of all the authors. All the authors gave approval to the final version of the manuscript. VKH performed and interpreted 3D-RISM calculations, docking and MD simulations. DR performed and interpreted quantum chemical calculations.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10822_2019_239_MOESM1_ESM.pdf (1.8 mb)
Supplementary file1 (PDF 1853 kb)


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Authors and Affiliations

  1. 1.Department of Mechanical EngineeringUniversity of AlbertaEdmontonCanada
  2. 2.Departments of Biological Sciences and Computing ScienceUniversity of AlbertaEdmontonCanada
  3. 3.Nanotechnology Research CentreEdmontonCanada

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