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.
Lipid droplets (LD’s) are organelles that play a key role in metabolism and human physiology, storing energy for cells to use when needed. Defects in LD metabolism can cause diseases such as obesity and lipodystrophy. LDs have a single phospholipid layer exterior and hold triglycerides and other lipids. Several different proteins are also found in the phospholipid exterior of an LD, for example GPAT (glycerol‐3‐phosphate O‐acyltransferase). LDs are assembled at the surface of the endoplasmic reticulum by the seipin protein complex, with the LD forming at the seipin site similar to “blowing a bubble”. We are undergraduate students at various levels in our training and have not encountered LDs in our coursework. However, we believe they are an important and intriguing model for teaching many introductory and more advanced biology and chemistry concepts. We designed a 3D printed model of the seipin complex (based on PDB file 6DS5, Yan 2018) that can be used in undergraduate teaching. This model, along with online videos and other tools, can be used to teach many topics through a hands‐on approach to learning. Topics we learned about while building our models and through the use of other materials included: protein structure, protein complexes, metabolism and its connection to different diseases, basic chemical structures, metabolic pathways, cellular structures, computational visualization of proteins, and the utilization of online tools such as the Protein Databank. LDs can be connected to content in many courses, including General Biology, General Chemistry, Biochemistry, Organic Chemistry, Genetics, Cell Biology and Physiology. Instructions for printing a copy of this model along with a list of other teaching resources can be made available to anyone who is interested.
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