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Document Type
Conference Proceeding
Publication Date
2025
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. PD might cause the dysfunctions of motor neuron in patients. Although the causes of PD still remain to be elucidated, multifactorial pathogenesis have been suggested. Currently available single-targeted drugs only provide symptoms-relieving benefits, but not delay or reverse the progress of PD. Thus, the "one-compound-multi-target ligands" strategy might be a promising strategy for the development of new drug for 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 a series of hybrids as the multifunctional candidates, targeting MEF2D, GSK3β and/or MAO-B. Encouragingly, some of these candidates have exhibited with reasonable pharmacokinetic properties with low cytotoxicity. Particularly, two of these novel hybrids, hybriding indolio-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. Moreover, several of these compounds significantly inhibit over-expression of alpha-synuclein in iPC12-A53Tcells. 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
Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. PD might cause the dysfunctions of motor neuron in patients. Although the causes of PD still remain to be elucidated, multifactorial pathogenesis have been suggested. Currently available single-targeted drugs only provide symptoms-relieving benefits, but not delay or reverse the progress of PD. Thus, the "one-compound-multi-target ligands" strategy might be a promising strategy for the development of new drug for 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 a series of hybrids as the multifunctional candidates, targeting MEF2D, GSK3β and/or MAO-B. Encouragingly, some of these candidates have exhibited with reasonable pharmacokinetic properties with low cytotoxicity. Particularly, two of these novel hybrids, hybriding indolio-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. Moreover, several of these compounds significantly inhibit over-expression of alpha-synuclein in iPC12-A53Tcells. These multi-functional compounds might be the candidates for the development of new generation of anti-PD leads via synergistically acting on multiple targets.
Recommended Citation
Mak, S. (2025). Pharmacological elucidation of novel frug-leads for the treatment of Parkinson's disease through multiple tergets. Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. PD might cause the dysfunctions of motor neuron in patients. Although the causes of PD still remain to be elucidated, multifactorial pathogenesis have been suggested. Currently available single-targeted drugs only provide symptoms-relieving benefits, but not delay or reverse the progress of PD. Thus, the "one-compound-multi-target ligands" strategy might be a promising strategy for the development of new drug for 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 a series of hybrids as the multifunctional candidates, targeting MEF2D, GSK3β and/or MAO-B. Encouragingly, some of these candidates have exhibited with reasonable pharmacokinetic properties with low cytotoxicity. Particularly, two of these novel hybrids, hybriding indolio-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. Moreover, several of these compounds significantly inhibit over-expression of alpha-synuclein in iPC12-A53Tcells. These multi-functional compounds might be the candidates for the development of new generation of anti-PD leads via synergistically acting on multiple targets.. Retrieved from https://repository.vtc.edu.hk/thei-dfhs-sp/37