Implication of Caspase-3 as a Common Therapeutic Target for Multineurodegenerative Disorders and Its Inhibition Using Nonpeptidyl Natural Compounds

Abstract

Caspase-3 has been identified as a key mediator of neuronal apoptosis. The present study identifies caspase-3 as a common player involved in the regulation of multineurodegenerative disorders, namely, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The protein interaction network prepared using STRING database provides a strong evidence of caspase-3 interactions with the metabolic cascade of the said multineurodegenerative disorders, thus characterizing it as a potential therapeutic target for multiple neurodegenerative disorders. In silico molecular docking of selected nonpeptidyl natural compounds against caspase-3 exposed potent leads against this common therapeutic target. Rosmarinic acid and curcumin proved to be the most promising ligands (leads) mimicking the inhibitory action of peptidyl inhibitors with the highest Gold fitness scores 57.38 and 53.51, respectively. These results were in close agreement with the fitness score predicted using X-score, a consensus based scoring function to calculate the binding affinity. Nonpeptidyl inhibitors of caspase-3 identified in the present study expeditiously mimic the inhibitory action of the previously identified peptidyl inhibitors. Since, nonpeptidyl inhibitors are preferred drug candidates, hence, discovery of natural compounds as nonpeptidyl inhibitors is a significant transition towards feasible drug development for neurodegenerative disorders.

Anti-Apoptotic Activity of Anthocyanins has Potential to inhibit Caspase-3 Signaling

“…The curcumin-caspase-3 interaction showed some amino acid residues that were Arg179, His237, Gln283, Ala284, Tyr338, Ser339, Trp340, Arg341, Phe381 and Ser343. Luteolin interacted with the Arg179, Ser236, Gln283, Tyr338, His237, Cys285, Tyr338, Ser339, Arg341, and Phe381 of caspase-3 [13]. Our study found that all anthocyanins except malvidin-3-Oglucoside bound to caspase-3 protein in Arg164, Tyr197, and Pro201.…”

“…Some compounds have been identified as caspase inhibitor. They are rosmarinic acid, curcumin, luteolin, huperzine A, quercetin, resveratrol, bilobalide, EGCG, apigenin, berberine, and chitosan [13]. Flavonoid inhibits caspase-3 activity in MDA-MB-231 cells in in-vitro study [14].…”

GardeninA confers neuroprotection against environmental toxin in aDrosophilamodel of Parkinson’s disease

“…Previous studies have shown that flavonoids can function as specific activators or inhibitors of caspases 44,45 . Inhibitors against different caspases have been shown to rescue neuronal deaths in several experimental PD models 41,73 .…”

“…Previous studies have indicated the involvement of caspases in inducing the death of DA neurons leading to PD pathogenesis 41,42 . Specifically, the activation of one of the downstream executioner caspases, caspase-3 has been associated with apoptotic cell death resulting in neuronal demise 43 .…”

Inhibition of C298S mutant of human aldose reductase for antidiabetic applications: Evidence from in silico elementary mode analysis of biological network model

“…Quantum Mechanical Molecular Mechanical (QM/MM) docking strategy was used to determine the probable inhibitors of ahAR. Autodock4.2, a standalone software was used for the docking of all the selected compounds with the energy minimized modeled enzyme‐structures . Gasteiger type of charges and MMFF94 force field were used for the compounds and energy minimization of the ligands, respectively.…”