Identification of Potential Peptide Inhibitors of ACE-2 Target of SARS-CoV-2 from Buckwheat & Quinoa.

It is well established fact that peptides from various foods offer human health benefits displaying diverse functionalities. Millets considered as super foods is a major alternative in recent days for traditional diet being rich in proteins and fibre along with trace minerals and vitamins. In this connection, proteins from Buckwheat and Quinoa were digested by in vitro simulation digestion for the generation of peptides, analyzed by nLC-MS/MS and the functional annotations of the identified proteins/peptides were carried out. The study led to the identification of 34 small peptides and their parent proteins clustered into 4 gene functional groups and their localization prediction indicated their involvement in energy metabolism, transport and storage. Interestingly, the identified peptides maximally displayed DPP-IV and ACE inhibitions. The present study was extended to unravel ACE-2 inhibition targeting COVID-19 by selecting ACE-2-Spike binding domain for molecular docking studies. The NWRTVKYG interacted with the ACE-2-Spike interface displaying the feasible binding energy (- 213.63) and docking score (- 12.43) and the MD simulation revealed the ability of the peptide in stabilizing the protein-peptide composite. The present investigation thus establishes newer vista for food derived peptides having ACE-2 inhibitory potential as tentative strategy for SARS-CoV-2 therapeutics.

In silico and In vivo Evaluation of Oxidative Stress Inhibitors Against Parkinson's Disease using the C. elegans Model.

BACKGROUND: Parkinson's disease ranks second, after Alzheimer's as the major neurodegenerative disorder, for which no cure or disease-modifying therapies exist. Ample evidence indicate that PD manifests as a result of impaired anti-oxidative machinery leading to neuronal death wherein Cullin-3 has ascended as a potential therapeutic target for diseases involving damaged anti-oxidative machinery. OBJECTIVE: The design of target specific inhibitors for the Cullin-3 protein might be a promising strategy to increase the Nrf2 levels and to decrease the possibility of "off-target" toxic properties. METHODS: In the present study, an integrated computational and wet lab approach was adopted to identify small molecule inhibitors for Cullin-3. The rational drug designing process comprised homology modeling and derivation of the pharmacophore for Cullin-3, virtual screening of Zinc natural compound database, molecular docking and Molecular dynamics based screening of ligand molecules. In vivo validations of an identified lead compound were conducted in the PD model of C. elegans. RESULTS AND DISCUSSION: Our strategy yielded a potential inhibitor; (Glide score = -12.31), which was evaluated for its neuroprotective efficacy in the PD model of C. elegans. The inhibitor was able to efficiently defend against neuronal death in PD model of C. elegans and the neuroprotective effects were attributed to its anti-oxidant activities, supported by the increase in superoxide dismutase, catalase and the diminution of acetylcholinesterase and reactive oxygen species levels. In addition, the Cullin-3 inhibitor significantly restored the behavioral deficits in the transgenic C. elegans. CONCLUSION: Taken together, these findings highlight the potential utility of Cullin-3 inhibition to block the persistent neuronal death in PD. Further studies focusing on Cullin-3 and its mechanism of action would be interesting.

Glycogen synthase kinase-ß3 in ischemic neuronal death.

Glycogen synthase kinase 3ß (GSK-3ß) is implicated in diverse cellular processes such as cell signaling and survival. Accumulating lines of evidence indicate that increased GSK-3ß activity contributes to neuronal death and pathogenesis of ischemic stroke. Considering predominant roles of GSK-3ß in neuronal apoptosis, modulation of this protein kinase is a reliable strategy for ischemic neuroprotection. In this review, we survey and synthesize the current knowledge about the role of GSK-3ß in neuroprotection following the ischemic stroke.

In silico identification of potential dynamin-related protein 1 antagonists: implications for diseases involving mitochondrial dysfunction.

Mitochondria are the center of metabolism and the critical role of aberrant mitochondrial fission in the onset and progression of a wide range of human diseases such as neurodegenerative disorders, cardiovascular disease, ischemic stroke and diabetes, is slowly becoming recognized. Under physiological conditions, mitochondrial structure is predominantly regulated by cycles of fusion and fission, which is very crucial for the maintenance of cellular homeostasis. Dynamin-related protein 1 is a GTPase that catalyzes the process of mitochondrial fission and is also associated with the excessive fragmentation of mitochondria, impaired mitochondrial dynamics and cell death. Hence, identification of potent and selective antagonists is prerequisite to successfully exploit the therapeutic effects of Drp1 inhibition. In this study, an integrated in silico strategy that includes homology modeling, pharmacophoric, docking analysis and molecular dynamics simulations was employed in designing the potential Drp1 inhibitors. A homology model of Drp1 was generated employing crystal structure of dynamin protein as a template. Pharmacophoric features were developed for the GTPase domain of dynamin-related protein 1 and were used to screen ZINC-database. The obtained hits were docked to the same domain. The binding mode analysis of these ligands showed all the essential binding interactions required in the inhibition of Drp1. Furthermore, explicit solvent simulations were carried out using the two most potential hits to validate the docking analysis and to study the overall stability of the binding site interactions. The present study not only provides a structural model of Drp1 for rational design of apoptotic inhibitors, but also identifies six potential compounds for further development.

Generation of pharmacophore and atom based 3D-QSAR model of novel isoquinolin-1-one and quinazolin-4-one-type inhibitors of TNFα.

In the present report, 3D-QSAR analysis was executed on the previously synthesized and evaluated derivatives of isoquinolin-1-ones and quinazolin-4-ones; potent inhibitors of tumor necrosis factor α (TNFα). Statistically significant 3D-QSAR models were generated using 42 molecules in the training set. The predictive ability of models was determined using a randomly chosen test set of 16 molecules, which gave excellent predictive correlation coefficients for 3-D models, suggesting good predictive index. Pharmacophore prediction generated a five point pharmacophore (AAHRR): two hydrogen bond acceptor (A), one hydrophobic (H) and two ring (RR) features. This pharmacophore hypothesis furnished a statistically meaningful 3D-QSAR model with partial least-square (PLS) factors seven having R2=0.9965, Q2=0.6185, Root Mean Squared Error=0.4284 and Pearson-R=0.853. Docking study revealed the important amino acid residues (His 15, Tyr 59, Tyr 151, Gly 121 and Gly 122) in the active site of TNFα that are involved in binding of the active ligand. Orientation of the pharmacophore hypothesis AAHRR.25 corresponded very closely with the binding mode recorded in the active site of ligand bound complex. The results of ligand based pharmacophore hypothesis and atom based 3D-QSAR furnished crucial structural insights and also highlighted the important binding features of isoquinolin-1-ones and quinazolin-4-ones derivatives, which may provide guidance for the rational design of novel and more potent TNFα inhibitors.