In Silico Analysis Determining the Binding Interactions of NAD(P)H: Quinone Oxidoreductase 1 and Resveratrol via Docking and Molecular Dynamic Simulations

Abstract

Objective: NAD(P)H: Quinone oxidoreductase1 (NQO1) plays a crucial role in cellular defense against oxidative stress. Overexpression of NQO1 is linked to various cancer pathways. Despite its potential, the actual mechanisms to inhibit NQO1 and increase the efficacy of standard therapeutic options are not yet established. Resveratrol is an anti-cancer polyphenol found in dietary products and red wine. The objective of this investigation is to employ in silico methods to explore how resveratrol interacts with NQO1.

Materials and methods: Docking analysis of resveratrol against NQO1 was performed using Glide. The most efficiently docked complex was characterized and analyzed by measuring intermolecular (IM) hydrogen (H)-bonds and binding energy values, additional hydrophobic, and electrostatic interactions. IM interaction between complexed protein and compound was demonstrated using LigPlot+ and the Schrödinger ligand interaction module. Molecular dynamics tools were employed to examine the physical movement of molecules to evaluate how macromolecular structures relate to their functions.

Results: The results of this investigation depicted a strong affinity of resveratrol against NQO1 followed by MD simulations (NQO1-resveratrol complex-binding energy: -2.847kcal/mol). Resveratrol's robust binding affinity through docking and molecular dynamic simulations highlights a significant change around 90 ns. The H-bonds number was inversely linked with the resveratrol-NQO1 complex stability. The NQO1-Resveratrol complex displayed dynamic motion, as revealed by porcupine projections, indicating alterations in its movement and flexibility.

Conclusion: The present in silico analysis suggests a possible alteration in resveratrol's orientation in the protein binding pocket. The findings encourage further investigation, including validation using in vitro and in vivo assays.

Keywords: In silico Analysis; Molecular Dynamic Simulation; NQO1; Oxidative Stress; Resveratrol.

Figure 1.

Binding energies and other interaction studies of the NQO1-resveratrol complex. (A) The NQO1-resveratrol complex exhibited IM hydrogen bonding, electrostatic interactions, and hydrophobic interactions. The 2D representation was generated using the ligand interactions module of Schrödinger. (B) The NQO1-resveratrol complex displayed its 2D interaction pattern through the utilization of the LigPlot+ tool and BIOVIA Discovery Studio 4.5 Visualizer (BIOVIA, San Diego, CA, USA).

Figure 2.

Root mean square deviation of the NQO1-resveratrol complex. The conformational stability of the NQO1 protein’s Apo and Holo states was assessed over a 100 nanoseconds (ns) duration of molecular dynamics simulation using the following analyses: (A) Backbone-RMSD of the NQO1-resveratrol complex. (B) Cα-RMSF profile of the NQO1-resveratrol complex. (C) Radius of gyration (Rg) profile of the NQO1-resveratrol complex. (D) Solvent accessible surface analysis (SASA) of the NQO1-resveratrol complex.

Figure 3.

H-bond analysis of the NQO1-resveratrol complex. (A) The protein-ligand contacts within the NQO1-resveratrol complex throughout the 100 ns simulation are visualized through a stacked bar chart. (B) The fluctuations in hydrogen bond interactions within the NQO1-resveratrol complex during the 100 ns simulation are indicated by blue lines. (C) Following the MD simulations, interactions including IM hydrogen bonding, electrostatic, and hydrophobic contacts are depicted within the NQO1-resveratrol complex. This graphical representation was generated using the ligand interaction module of Schrödinger.

Figure 4.

Principal component analysis of the NQO1-resveratrol complex. (A) The projection of trajectories (PC1 and PC2) is symbolized by the cloud. (B) A comparative analysis of cross-correlation matrices for the backbone atoms within the NQO1-resveratrol complex was conducted using PCA. (C) The individual components within the NQO1-resveratrol complex are visually represented through sharp porcupine plot curves in a vectorial manner.

Figure 5.

Schematic representation of the mechanism of resveratrol interaction with NQO1 and its implication as a potential cancer therapy. Upon dysregulation of Keap1/NRF2 pathways driven by pro-tumorigenic signaling in cancer cells, NQO1 transcription and translation are increased. We suggest upon binding with resveratrol, NQO1 is downregulated, leading to an elevated level of intracellular ROS resulting in increased cancer cell death.