Screening study IDs inhibitor of key COVID virus enzyme
Molecule could serve as component of new treatments for COVID-19

Date:
January 26, 2022
Source:
DOE/Brookhaven National Laboratory
Summary:
A study reports the discovery of a molecule with significant
potential to disable the COVID-19 virus. The molecule was identified
using high- throughput virtual screening -- a search through a
library of 6.5 million in-stock compounds that could quickly be
scaled up for drug production using some of the nation's most
powerful supercomputers and other research tools.



FULL STORY ==========================================================================
When the COVID-19 pandemic hit, scientists across the U.S. Department
of Energy's (DOE) national laboratory complex turned to the nation's
most powerful supercomputers and other tools to discover molecules that
might treat the disease. A study published in the Journal of Chemical Information and Modeling reports the discovery of a molecule with
significant potential to disable the virus.


==========================================================================
The molecule was identified using high-throughput virtual screening --
a search through a library of 6.5 million in-stock compounds that could
quickly be scaled up for drug production. The team used computer-based molecular docking studies to identify molecules that could bind to
certain targets on the virus's main protease (Mpro) -- an enzyme the
virus uses to make copies of itself. They also conducted high-throughput laboratory screening experiments, structural studies, and molecular
dynamics simulations to learn how these potential inhibitors and the
enzyme interact. The goal was to find molecules that could jam up the
enzyme's function, which would stop the virus from replicating.

The computational team, which included scientists from the Computational Science Initiative (CSI) at DOE's Brookhaven National Laboratory,
identified 72 candidate molecules with potential to inhibit Mpro. Other
teams ran laboratory experiments testing those molecules' ability
to inhibit the virus. Structural studies using, for example, x-ray crystallography revealed how the candidate molecules fit together with
the virus enzyme. Additional computer-based simulations provided details
about how those interactions alter the enzyme.

The paper describes how the most promising candidate, known as MCULE- 5948770040, binds with Mpro and changes its shape in a way that inhibits
the enzyme's function. Future experiments will explore whether the
molecule can be developed into a new drug for treating COVID-19.

"Scientists from Brookhaven's CSI played an important role in generating
and analyzing large volumes of data that led to scientific insight,"
said Shantenu Jha, one of the corresponding authors on the paper, who
holds a joint appointment with Brookhaven and Rutgers University. "CSI
folks also established the 'software infrastructure' to support the
large-scale computations," he said.

Given the urgency of the pandemic, "this was a very high-intensity
project with a great level of 'learning while doing,'" Jha noted.

CSI's Hubertus Van Dam, another study co-author, agreed, saying he was
inspired by "tackling, for me, a new set of problems with a new set of
methods in a large team." The team for this paper included scientists
from five national laboratories and four collaborating universities,
all supported by the DOE Office of Science through the National Virtual Biotechnology Laboratory (NVBL). NVBL is a consortium of DOE national laboratories focused on response to COVID-19, with funding provided by
the Coronavirus CARES Act.

Kerstin Kleese Van Dam, director of CSI at Brookhaven, served as leader
of Brookhaven's role in the NVBL medical therapeutics project.

"A key weapon in our arsenal in the fight against COVID-19 are medicines
to treat those infected," she said. "The NVBL medical therapeutics project brought to bear the combined might of DOE scientists, and key experimental
and computational facilities to discover new COVID treatments.

"This paper describes not only some of our successes, but also gives
a glimpse behind the scenes at the scientific ingenuity needed to make
those exciting discoveries possible." The research was also supported
by the DOE-Exascale Computing Project.

========================================================================== Story Source: Materials provided by
DOE/Brookhaven_National_Laboratory. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Austin Clyde, Stephanie Galanie, Daniel W. Kneller, Heng Ma,
Yadu Babuji,
Ben Blaiszik, Alexander Brace, Thomas Brettin, Kyle Chard, Ryan
Chard, Leighton Coates, Ian Foster, Darin Hauner, Vilmos Kertesz,
Neeraj Kumar, Hyungro Lee, Zhuozhao Li, Andre Merzky, Jurgen
G. Schmidt, Li Tan, Mikhail Titov, Anda Trifan, Matteo Turilli,
Hubertus Van Dam, Srinivas C.

Chennubhotla, Shantenu Jha, Andrey Kovalevsky, Arvind Ramanathan,
Martha S. Head, Rick Stevens. High-Throughput Virtual Screening
and Validation of a SARS-CoV-2 Main Protease Noncovalent
Inhibitor. Journal of Chemical Information and Modeling, 2021; 62
(1): 116 DOI: 10.1021/acs.jcim.1c00851 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220126133143.htm

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