A new coronavirus causing an acute respiratory syndrome (SARS‐CoV‐2) emerged in late 2019 and has been responsible for the outbreak of coronavirus disease 2019 (COVID‐19). Symptoms of COVID‐19 range from mild to severe, including respiratory symptoms, systemic inflammatory responses, and even death. Currently, remdesivir is the only FDA‐approved therapeutic agent to treat COVID‐19, although it shows limited efficacy. We were interested in learning about the drug design process for a novel virus. We focused on drug research targeting the SARS‐CoV‐2 main protease, known as nsp5 or Mpro. The nsp5 protease is an enzyme critical for viral replication, with ebselen, cinanserin, and N3 being lead compounds identified as possible effective drugs (Jin, 2020). Starting with these chemical drug structures, we used an in silico drug design process to explore how to modify and refine these drugs. Our goal was to make the compounds more drug‐like, according to Lipinski's and Veber's rules. Using the crystal structure file 6YB7 from the Protein Data Bank (PDB), we focused on the protease active site, defined by amino acids His41, Met49, Asn142, Cys145, His164, Met165, Glu166, Pro168, and Gln189. Cys145 is especially important, as it is the target for irreversible covalent inhibitors. Based on this information, we used molecular docking software to first re‐dock these drugs into the nsp5 protease. We then made changes to the structures of the lead compounds, docked those new compounds, and used the energetic information to continue the refinement process. Once we completed our own drug design explorations, we created a three‐dimensional printed model of the full nsp5 protease, with the key amino acids highlighted. We also created a three‐dimensional model zoomed in on the active site, with the different drugs fitting into that active site model. Here, we present what we learned about the drug design process for a novel virus such as SARS‐CoV‐2. Our docking protocols and models are useful for teaching the fundamentals of drug design and about modern drug discovery and design processes.
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system which may be influenced by gut bacteria-produced metabolites. We have shown that isoflavone-metabolizing bacteria are less abundant in MS patients as compared to healthy individuals and loss of these bacteria leads to increased disease severity in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Isoflavone metabolites can modulate the immune response through binding to estrogen receptors α and β (ERα and ERβ). Thus, we aim to investigate the role of ERα and ERβ in isoflavone-mediated disease protection in EAE by determining ER expression on immune and intestinal epithelial cells as well as receptor specificity for isoflavone-mediated protection in EAE. We hypothesize that isoflavone metabolites induce an anti-inflammatory state via engagement of ERs and that reduction/absence of these molecules may predispose patients to MS development and/or severity. To test this, we administered an isoflavone-containing diet to mice and induced EAE. Mice fed an isoflavone-containing diet developed milder disease than mice fed an isoflavone-free diet while also exhibiting higher expression of ERα, but not ERβ, in the gut. Surprisingly, there was no change in ERβ expression in splenic CD4+ or CD8+ T-cells of mice fed an isoflavone-free versus an isoflavone-containing diet. Mice administered equol also exhibited milder disease than controls. Ongoing experiments using chemical or genetic inhibition of ERα and ERβ signaling will determine the role of these receptors in EAE disease amelioration. Our results suggest that bacterial metabolism of isoflavones leads to EAE disease suppression through utilization of estrogen receptors. Supported by grants from NIH (T32AI007485, 1R01AI137075-01) and a generous gift from Margaret Heppelmann and Michael Wacek.
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