CABS Webinar: COVID-19 Small Molecule Drug Discovery

Date: February 27, 2021 @ 1:30 pm – @ 5:30 pm
Location: Online Zoom conference

COVID-19 Small Molecule Drug Discovery Webinar

Organized by CABS Science & Technology Committee

COVID-19, caused by SARS-CoV-2, is a global health and economic catastrophe. The main protease (Mpro) and the papain-like protease (PLPro) are essential for SARS-CoV-2 replication and thus are the compelling targets for small molecule anti-COVID-19 drug discovery. Regulating proteases in other viruses has been proven to be a successful pathway in the treatment of virus-caused diseases such as HIV and HCV. With progress on the understanding of these protein structures by collecting their high quality X-ray data, drug design and medicinal chemistry are being accelerated by computational tools to efficiently identify potent small molecule inhibitors. It’s of great hope that some breakthrough discovery may be achievable in a short period of time through integrated efforts and collaborations. We are happy to bring these scientists and specialists together to present you a CABS online webinar about COVID-19 small molecule drug discovery. You will hear their recent discovery and thoughts about how we should conquer this virus. You are welcome to join and we are looking forward to your participation and scientific discussion. 

Date: February 27th 2021, Saturday, 1:30-5:30 PM (Pacific Time).



1:30 to 1:35 PM Welcome Remarks from CABS. Ken Zhang, PhD, Co-Chair, STC, CABS.

1:35 to 2:15 PM Drug Repurposing for Treatment of COVID-19 and Inflammation-related Diseases Guided by Novel Computational Algorithms. Chang-Guo Zhan, PhD, Endowed Professor of Pharmaceutical Sciences and Director of Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky.

Abstract: In this talk, I will briefly talk about the applications of our recently developed novel computational algorithms to small-molecule drug repurposing for treatment of COVID-19 and inflammation-related diseases. Particularly for COVID-19, we have identified drugs suitable for the antiviral treatment targeting SARS-CoV-2 main protease and anti-inflammatory treatment of the COVID-19 hyperinflammatory (or cytokine storm).

2:15 to 2:55 PM How to Stop the Heart of a Virus: Specific Inhibitors and Clinical Drug Repurposing to Target SARS-CoV-2 Main Protease using X-rays, Neutrons and Computation. Andrey Kovalevsky, PhD, Senior R&D Scientist, Neutron Scattering Division, Oak Ridge National Laboratory.

Abstract: Computer-assisted and structure-guided drug design strategies rely on atomic scale understanding of the target biomacromolecule traditionally derived from X-ray crystallographic data collected at cryogenic temperatures. Conventional protein X-ray crystallography studies are limited by cryo-artifacts and its inability to locate the functional hydrogen atoms crucial for understanding chemistry occurring in enzyme active sites. Neutrons are an ideal probe to observe the protonation states of ionizable amino acids at near-physiological temperature, such as the non-canonical Cys-His catalytic dyad of SARS-CoV-2 Mpro. Our X-ray crystal structures of Mpro collected at near-physiological temperatures brought rapid insights into the reactivity of the catalytic cysteine, malleability of the active site, and binding modes with clinical protease inhibitors. The neutron crystal structures of ligand-free and ligand-bound Mpro were determined allowing the direct observation of protonation states of a catalytic site in a cysteine protease for the first time. At rest, the catalytic Cys-His dyad exists in the reactive zwitterionic state, with charged thiolate and doubly protonated imidazole side chains, instead of the anticipated neutral state. Ligand binding results in modulation of the protonation states, retaining the overall electric charge of the active site cavity. Our research is providing real-time data for atomistic design and discovery of Mpro inhibitors to combat the COVID-19 pandemic and prepare for future threats from pathogenic coronaviruses.

2:55 to 3:35 PM Targeting the SARS-CoV-2 Main Protease for Drug Discovery. Wenshe Ray Liu, PhD, Gradipore Chair and Professor in Chemistry, Texas A&M University.

Abstract: By targeting the essential main protease of SARS-CoV-2, the COVID-19 pathogen, a series of small molecule antivirals have been developed and tested on their inhibition of SARS-CoV-2 infection of human cells. Potent inhibitors include bepridil, a FDA approved medicine and a number of aldehyde-based compounds that form a covalent bond with the catalytic cysteine in the enzyme active site.

3:35 to 3:40 PM Break.

3:40 to 4:20 PM Drug Discovery Targeting SARS-CoV-2 Main Protease and Papain-like Protease. Jun Wang, PhD, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona.

Abstract: SARS-CoV-2 encodes two viral proteases, the main protease (Mpro) and the papain-like protease (PLPro). These two proteases cleave the viral polyproteins during the viral replication and are validated antiviral drug targets. In addition, PLpro has been shown to suppress host immune response. In this presentation, I will introduce our efforts in developing inhibitors targeting Mpro and PLpro. Through high-throughput screening and subsequent structure-based drug design, several inhibitors have been identified with both potent enzymatic inhibition and cellular antiviral activity against SARS-CoV-2. To elucidate their mechanism of action, we solved multiple X-ray co-crystal structures of Mpro and PLpro with inhibitors. The significance of our study is the discovery of dual inhibitors targeting both viral Mpro and host cathepsin L, both of which are critical for the viral replication.

4:20 to 5:00 PM Remdesivir’s Inhibition of SARS-CoV-2 RNA Polymerization. Jason Perry, PhD, Senior Director, Structural Chemistry Department, Gilead Sciences.

Abstract: (TBD).

5:00 to 5:30 PM Panel Discussion. Host and All Speakers.

Speakers Background:

Dr. Chang-Guo Zhan is an Endowed Professor of Pharmaceutical Sciences and Director of Molecular Modeling and Biopharmaceutical Center in the College of Pharmacy, University of Kentucky. He also serves as Director of Chemoinformatics and Drug Design Core of the Center for Pharmaceutical Research and Innovation (CPRI) at the University of Kentucky.

With a research activity ranging from basic sciences to practical clinical applications, Dr. Zhan has published more than 390 scientific papers in peer-reviewed journals and has 55 patents or patent applications. Dr. Zhan’s current research interests are mainly focused on rational design, discovery, and development of novel therapeutics, as well as drug repurposing. Two of designed novel therapeutic candidates designed by him have completed Phase II clinical trials in humans; one received the Breakthrough Therapy designation by the FDA and is currently in preparation of Phase III clinical trial. Another long-acting protein drug candidate is heading to Phase I clinical trial. He has been very successful in securing nationally competitive research funding from the NIH, NSF, DoD, and other funding resourcesincluding more than $33M as PI since 2003.

At the University of Kentucky, Dr. Zhan was named as University Research Professor by the President and Board of Trusty in 2016, and won Kirwan Prize (the highest research award at the University of Kentucky) in 2017. He was a winner of 2005 Emerging Computational Technology Prize, American Chemical Society (ACS) Division of Computers in Chemistry, and is the current recipient of the NIDA Translational Avant-Garde Award from the NIH. Dr. Zhan was elected AAPS Fellow in 2010, and won 2016 AAPS Research Achievement Award in Drug Discovery and Development Interface.

Dr. Andrey Kovalevsky is a structural biologist, biochemist and neutron instrument scientist at Oak Ridge National Laboratory (ORNL). His current research focuses on the atomic level understanding of protein function, structure-guided drug design and drug resistance utilizing biophysical methods in combination with molecular simulations. Kovalevsky studied organic chemistry and crystallography at Kharkov State University, Kharkov, Ukraine, receiving his M.Sc. degree with Honors, and worked as a Research Assistant at Nesmeyanov Institute of Organoelement Compounds, Moscow, Russia. He received his Ph.D. in Physical Chemistry from University at Buffalo, The State University of New York. He studied macromolecular crystallography, biochemistry and molecular biology while working as a Postdoctoral Associate at Georgia State University. He held a Director’s Postdoctoral Fellowship and a Staff Scientist position while at Los Alamos National Laboratory. Currently, Dr. Kovalevsky is a Senior R&D scientist at the Neutron Scattering Division (ORNL).

Dr. Wenshe Ray Liu received his BS degree from Peking University in 2000 and PhD degree from UCDavis in 2005. He did two year postdoc in Scripps and started his independent research career at Texas A&M University in 2007 as an assistant professor. He was promoted to Associate Professor in 2013 and then Full Professor in 2016. Dr. Liu is the current holder of Gradipore Chair in Chemistry at Texas A&M University. Dr. Liu was a previous director of the TAMU Chemistry Mass Spectrometry Laboratory. He is currently chairing the Chemical Biology division in the Chemistry Department and the director of the Texas A&M Drug Discovery Laboratory. He is leading a chemical biology and drug discovery research group. 

Dr. Jun Wang received the B.Sc in chemistry from Wuhan University in 2003, the M.Sc in chemistry from National University in Singapore in 2006, and Ph.D. in chemistry from University of Pennsylvania in 2010. He was a postdoc first at the University of Pennsylvania, then at UCSF.  He started his independent career as an assistant professor at the University of Arizona, College of Pharmacy in 2014. He was promoted to associate professor with tenure in 2020. The Wang Laboratory focuses on developing antivirals targeting drug-resistant viruses and emerging viruses, including influenza A and B viruses, enterovirus D68 (EV-D68), EV-A71, coxsackievirus, poliovirus, and the recently emerged SARS-CoV-2. 

Dr. Jason Perry is a Senior Director in the Structural Chemistry Department at Gilead Sciences.  As a member of the modeling group for nearly 15 years, he has contributed to over two dozen research programs.  His primary focus has been in the area of Antivirals, where he has helped in the discovery and characterization of five approved drugs.  Prior to joining Gilead, he was an Applications Scientist at Schrodinger for 11 years, where he worked with researchers all over the US in getting the most out of their modeling software.  He received his BA from Johns Hopkins and his PhD from Caltech, where he worked in the labs of Bill Goddard.

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