Event Title

Design and Synthesis of COVID-19 Antivirals Using Computer Modeling

Session Number

Project ID: MEDH 30

Advisor(s)

Dr. John Thurmond, Illinois Mathematics and Science Academy

Discipline

Medical and Health Sciences

Start Date

20-4-2022 9:10 AM

End Date

20-4-2022 9:25 AM

Abstract

The development of effective antiviral drugs for COVID-19 is ongoing. COVID Moonshot is an initiative that contributes to this goal. We aim to develop easily manufacturable antiviral drugs that can inhibit the SARS-CoV-2 main protease, Mpro. Using fragment-based drug discovery, which identifies low-molecular-weight ligands that bind to biologically important macromolecules, leads for the biological target were identified. We designed new molecules from our COVID Moonshot starting fragment, x1086, through modification of its bonds in SeeSAR, a 3D modeling software platform. Compounds with the best-estimated affinities from the 341 designed compounds were selected and data on their druglikeness and ADMETOX properties were gathered through swissADME and ADMETSAR, websites predicting physicochemical descriptors and ADMETox parameters (absorption, digestion, metabolism, excretion, and toxicity). We looked at Lipinski’s rules and human ether-à-go-go related genes (hERG inhibition), BBB permeability, CYP3A4 inhibition, and bioavailability. We submitted our best eight compounds to the COVID Moonshot Consortium for further testing and drug development and one was modified for synthesis. Additionally, an unsubmitted molecule was also synthesized with modifications. Their molecular structures were confirmed through Nuclear Magnetic Resonance (NMR) and their data was gathered though swissADME and ADMETSAR. Further synthesis of our other designed molecules are in progress.

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Apr 20th, 9:10 AM Apr 20th, 9:25 AM

Design and Synthesis of COVID-19 Antivirals Using Computer Modeling

The development of effective antiviral drugs for COVID-19 is ongoing. COVID Moonshot is an initiative that contributes to this goal. We aim to develop easily manufacturable antiviral drugs that can inhibit the SARS-CoV-2 main protease, Mpro. Using fragment-based drug discovery, which identifies low-molecular-weight ligands that bind to biologically important macromolecules, leads for the biological target were identified. We designed new molecules from our COVID Moonshot starting fragment, x1086, through modification of its bonds in SeeSAR, a 3D modeling software platform. Compounds with the best-estimated affinities from the 341 designed compounds were selected and data on their druglikeness and ADMETOX properties were gathered through swissADME and ADMETSAR, websites predicting physicochemical descriptors and ADMETox parameters (absorption, digestion, metabolism, excretion, and toxicity). We looked at Lipinski’s rules and human ether-à-go-go related genes (hERG inhibition), BBB permeability, CYP3A4 inhibition, and bioavailability. We submitted our best eight compounds to the COVID Moonshot Consortium for further testing and drug development and one was modified for synthesis. Additionally, an unsubmitted molecule was also synthesized with modifications. Their molecular structures were confirmed through Nuclear Magnetic Resonance (NMR) and their data was gathered though swissADME and ADMETSAR. Further synthesis of our other designed molecules are in progress.