Terpenoid analogues as putative therapeutic agents towards glutathione peroxidase (GPX4) in neurodegenerative disorders: a dynamic computational approach

Abstract

Carvacrol, a monoterpenoid phenolic phytochemical, a potent antioxidant, and neuroprotective agent is an emerging neuroprotective agent for neurodegenerative diseases (NDDs). Considering scarce information on carvacrol analogues, we hypothesized an in silico investigation emphasizing their preferential binding towards glutathione peroxidase (GPX4) as a target across different species for evaluating through preclinical to clinical studies (2OBI and 6HN3 for Homo sapiens; 5L71 for Mus musculus). Enrichment analysis suggests that ROC (0.59) and AUC (0.61) values have higher sensitivity and significant number of ranked actives. Extra Precision (XP) of 59 compounds was conducted, followed by molecular dynamics and trajectory analysis. Top three hits were chosen for each target i.e., 101203408, 101419546, 59294 (2OBI); 101419546, 100938426, and 28092 (6HN3); and 12059, 52434, 335 (5L71) implying high docking score. 101419546 is common among 2OBI and 6HN3 targets, indicating a multi-target approach. Trajectory analysis of hits provides a permissible range of RMSD, RMSF, Rgyr (∼1.3–2 Å, ∼0.84–1.09 Å, ∼15.05–15.29 Å). Overlapped dynamically simulated 3D-structures of Apo and complexes display significant conformational changes in RMSD of the complexes (∼1.40–2.0 Å) in contrast to Apo (∼1.3–1.8 Å), suggesting structural stability and compactness of the complexes within 45–90 ns. DCCM and PCA analysis shows positive correlation and residual clustering among residues of complexes. The establishment of firm H-bonding, favorable aromaticity and ADMET profile makes them promising drugs across various GPX4 targets among the species. Studies considering the targets across different species aids in anticipating and discovering a common compound for future NDDs therapeutics from bench to bedside.

Communicated by Ramaswamy H. Sarma

Keywords:

• Carvacrol analogues
• ferroptosis
• glutathione peroxidase 4
• in silico
• molecular dynamic simulation
• neuroprotection

Disclosure statement

All the authors declare no conflict of interest.

Ethical approval

This is an in-silico study and does not require ethical approval.

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Data availability statement

The X-RAY crystallized structure of the Glutathione peroxidase protein (GPX4) chosen was PDB-ID (2OBI, 6HN3, and 5L71) (2OBI - https://www.rcsb.org/structure/2OBI, 6HN3-https://www.rcsb.org/structure/6HN3, and 5L71-https://www.rcsb.org/structure/5L71). The protein preparation, modeling, docking and MD were performed on Maestro (release 2020-4). The carvacrol analogues were retrieved from PubChem database (http://pubchem.ncbi.nlm.nih.gov/). Using the Bio3d v.2.4-1.9000 (http://thegrantlab.org/bio3d/) package in R studio v1.4.1103, MD trajectories of protein-ligand complexes was obtained by examining the Dynamical Cross-Correlation Matrix (DCCM) and Principal Component Analysis (PCA) (https://rstudio.com/products/rstudio/download-commercial-desktop/).

The original information if needed can be provided on request.