title: 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, R(2) = .71 and [Formula: see text] = .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.
authors.affiliation: a CCG@cug Lab, School of Chemical Sciences , Central University of Gujarat , Gandhinagar 382030 , Gujarat , India.
authors.forename: Mohd
authors.initials: M
authors.lastname: Athar
authors.affiliation: a CCG@cug Lab, School of Chemical Sciences , Central University of Gujarat , Gandhinagar 382030 , Gujarat , India.
authors.forename: Mohsin Yousuf
authors.initials: MY
authors.lastname: Lone
authors.affiliation: b School of Health Sciences, Discipline of Pharmaceutical Sciences , University of KwaZulu-Natal , Westville, Durban 4000 , South Africa.
authors.forename: Vijay M
authors.initials: VM
authors.lastname: Khedkar
authors.affiliation: a CCG@cug Lab, School of Chemical Sciences , Central University of Gujarat , Gandhinagar 382030 , Gujarat , India.
authors.forename: Prakash Chandra
authors.initials: PC
authors.lastname: Jha
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D051267:NF-E2-Related Factor 2 / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D013450:Sulfones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D051267:NF-E2-Related Factor 2; D013450:Sulfones; C009873:divinyl sulfone
keywords: 3D-QSAR; ADME; Nrf2; OH-1; Parkinson disease; docking; pharmacophore