A Drug Repurposing Approach to Identify Therapeutics by Screening Pathogen Box Exploiting SARS-CoV-2 Main Protease.

Coronavirus disease-19 (COVID-19) is caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2) and is responsible for a higher degree of morbidity and mortality worldwide. There is a smaller number of approved therapeutics available to target the SARS-CoV-2 virus, and the virus is evolving at a fast pace. So, there is a continuous need for new therapeutics to combat COVID-19. The main protease (Mpro ) enzyme of SARS-CoV-2 is essential for replication and transcription of the viral genome, thus could be a potent target for the treatment of COVID-19. In the present study, we performed an in-silico screening analysis of 400 diverse bioactive inhibitors with proven antibacterial and antiviral properties against Mpro drug target. Ten compounds showed a higher binding affinity for Mpro than the reference compound (N3), with desired physicochemical properties. Furthermore, in-depth docking and superimposition revealed that three compounds (MMV1782211, MMV1782220, and MMV1578574) are actively interacting with the catalytic domain of Mpro . In addition, the molecular dynamics simulation study showed a solid and stable interaction of MMV178221-Mpro complex compared to the other two molecules (MMV1782220, and MMV1578574). In line with this observation, MM/PBSA free energy calculation also demonstrated the highest binding free energy of -115.8 kJ/mol for MMV178221-Mpro compound. In conclusion, the present in silico analysis revealed MMV1782211 as a possible and potent molecule to target the Mpro and must be explored in vitro and in vivo to combat the COVID-19.

The Interplay of the Unfolded Protein Response in Neurodegenerative Diseases: A Therapeutic Role of Curcumin.

Abnormal accumulation of misfolded proteins in the endoplasmic reticulum and their aggregation causes inflammation and endoplasmic reticulum stress. This promotes accumulation of toxic proteins in the body tissues especially brain leading to manifestation of neurodegenerative diseases. The studies suggest that deregulation of proteostasis, particularly aberrant unfolded protein response (UPR) signaling, may be a common morbific process in the development of neurodegeneration. Curcumin, the mixture of low molecular weight polyphenolic compounds from turmeric, Curcuma longa has shown promising response to prevents many diseases including current global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and neurodegenerative disorders. The UPR which correlates positively with neurodegenerative disorders were found affected by curcumin. In this review, we examine the evidence from many model systems illustrating how curcumin interacts with UPR and slows down the development of various neurodegenerative disorders (ND), e.g., Alzheimer's and Parkinson's diseases. The recent global increase in ND patients indicates that researchers and practitioners will need to develop a new pharmacological drug or treatment to manage and cure these neurodegenerative diseases.