Pharmacophore model prediction, 3D-QSAR and molecular docking studies on vinyl sulfones targeting Nrf2-mediated gene transcription intended for anti-Parkinson drug design

Abstract

Despite intense research efforts towards clinical and molecular causes of Parkinson disease (PD), the etiology of disease still remains unclear. However, recent studies have provided ample evidences that the oxidative stress is the key player that contributes a lot to dopaminergic (DAergic) neurodegeneration in brain. It is due to the discrepancy of antioxidant defence system of which nuclear factor erythroid 2-related factor 2 (Nrf2) signalling is of central contour. In the current study, potent heme oxygenase-1 agonists (Nrf2 signalling regulator), vinyl sulfones, were selected and an optimal pharmacophore model was brought forth which was examined using a decoy set by atom-based 3D-QSAR. The best four-feature model consists of two hydrogen bond acceptors and two aromatic rings, which has the highest correlation coefficient, R² = .71 and = .73 in QSAR. These ligands were further studied for molecular docking with Nrf2-keap protein to gain insight into the major binding motifs followed by analysing pharmacokinetic properties to evaluate their bioavailability dominance. From this study, it is concluded that vinyl sulfones could be ideal compounds for targeting Nrf2 pathway which in turn halt the PD progression. Hence, these can be considered as potential leads for drug development against the same.

Graphical abstract

Keywords:

• Parkinson disease
• Nrf2
• OH-1
• pharmacophore
• 3D-QSAR
• docking
• ADME

Acknowledgements

This work was supported by Department of Science & Technology (DST), New Delhi, under INSPIRE-JRF grant awarded to Mohd Athar. One of the authors (PCJ) would like to thank University Grants Commission (UGC) for providing start-up grants and Central University of Gujarat for providing basic computational facilities. We also thank Schrödinger for providing the Demo license of Schrödinger Suite, and especially Vinod Devarji for delivering valuable technical support that has tremendously helped in this study.

Disclosure statement

No potential conflict of interest was reported by the authors.