Document Type

Conference Proceeding

Publication Date

2024

Keywords

Parkinson’s disease, Multifunctional, Neuroprotection, GSK3β

Abstract

Parkinson’s disease (PD) are the second most common neurodegenerative disorder worldwide. PD might cause the dysfunctions of motor neuron in patients. Since PD is multifactorial neurodegenerative disorders, currently single-targeted drugs only provide symptoms-relieving benefits, but not delay the pathological progress to PD parents. Thus, the “one-compound-multi-target ligands” strategy might be focused for the development of novel candidates for treating PD. Recent studies have also demonstrated that glycogen synthase kinase-3β (GSK3β)/ myocyte enhancer factor 2D (MEF2D) and monoamine oxidase-B (MAO-B) might be important therapeutic targets for treating PD. Here, by using a sequential combination of ligand and structure-based virtual screening techniques, as well as molecular docking analysis, we designed and synthesized several hybrids as the multifunctional candidates, targetingMEF2D, GSK3β and/or MAO-B. Encouragingly, some of these candidates have exhibited with reasonable pharmacokinetic properties and low toxicity. Particularly, two of these novel hybrids, hybriding indolin-2-one core (pharmacophore of 3-substituted-2-indolin-ones compounds, MEF2 enhancer) and the propargyl (moiety of the irreversible MAO-B inhibitor, rasagiline) have shown promising inhibitory effects on GSK3β and MAO-B, respectively. These multi-functional compounds might be the candidates for the development of new generation of anti-PD leads via synergistically acting on multiple targets.

Source Publication

BioMed-2024

Download

Share

COinS