ABSTRACT
Corona viruses were first identified in 1931 and SARS-CoV-2 is the most recent. COVID-19 is a pandemic that put most of the world on lockdown and the search for therapeutic drugs is still on-going. Therefore, this study uses in silico screening to identify natural bioactive compounds from fruits, herbaceous plants and marine invertebrates that are able to inhibit protease activity in SARS-CoV-2(PDB: 6LU7). We have used various screening strategies such as drug likeliness, antiviral activity value prediction, molecular docking, ADME (absorption, distribution, metabolism, and excretion), molecular dynamics (MD) simulation and MM/GBSA (molecular mechanics/generalized born and surface area continuum solvation). 17 compounds were shortlisted using Lipinski’s rule. 5 compounds revealed significantly good predicted antiviral activity values and out of them only 2 compounds, Macrolactin A and Stachyflin, showed good binding energy values of -9.22 and -8.00 kcal/mol within the binding pocket, catalytic residues (HIS 41 and CYS 145) of Mpro. These two compounds were further analyzed for their ADME properties. The ADME evaluation of these 2 compounds suggested that they could be effective as therapeutic agents for developing drugs for clinical trials. MD simulations showed that protein-ligand complexes of Macrolactin A and Stachyflin were stable for 100 nano seconds. The MM/GBSA calculations of Mpro – Macrolactin A complex indicated higher binding free energy (-42.58 ± 6.35 kcal/mol) with Mpro protein target receptor (6LU7). DCCM and PCA analysis on the residual movement in the MD trajectories confirmed the good stability on Macrolactin A bound state of 6LU7. This signify the stable conformation of 6LU7 with high binding energy with Macrolactin A. Thus, this study showed that Macrolactin A could be an effective therapeutical agent for SARS-CoV-2protease (6LU7) inhibition. Additional in vitro and in vivo validations are needed to determine efficacy and dose of Macrolactin A in biological systems.
Subject(s)
Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
We postulate that similar to bacteria, adult stem cells may also exhibit an innate defense mechanism to protect their niche. Here, we provide preliminary data on stem cell based innate defense against a mouse model of coronavirus, murine hepatitis virus-1 (MHV-1) infection. In a mouse model of mesenchymal stem cell (MSC) mediated Mycobacterium tuberculosis (Mtb) dormancy, MHV-1 infection in the lung exhibited 20 fold lower viral loads than the healthy control mice, suggesting the potential enhancement of an anti-MHV-1 defense by Mtb. This defense mechanism involves the in vivo expansion and reprogramming of CD271+MSCs in the lung to an enhanced stemness phenotype. The reprogrammed MSCs facilitate the activation of stemness genes, intracellular Mtb replication, and extracellular release of Mtb. The conditioned media of the reprogrammed MSCs exhibit direct anti-viral activity in an in vitro model of MHV-1 induced toxicity to type II alveolar epithelial cells. Thus, our data suggest that reprogrammed MSCs exert a unique innate defense against MHV-1 by activating dormant Mtb. The molecular details of this anti-viral defense mechanism against coronavirus could be further studied to develop a vaccine against COVID-19.