Last year we highlighted work
done by a consortium called Open Source Antibiotics to find fragment hits
against antibacterial targets. A similar effort has now launched to discover leads
for COVID-19. And those involved have done so with breathtaking speed and openness.
A group of researchers including Dave
Stuart, Martin Walsh, and Frank von Delft (Diamond Light Source) has performed
a fragment screen against crystals of the main protease (MPro) of
SARS-CoV-2, the virus that causes COVID-19. Even before fully analyzing all of the
data, let alone publishing it on bioRxiv, they are making it available here,
with promises of frequent updates.
MPro is a cysteine
protease essential for viral viability. The first crystal structure of the
protein was solved in January and posted on bioRxiv late last month. The Diamond
researchers synthesized the gene and used it to produce protein that crystallized
and diffracted to high (1.39 Å) resolution. Importantly, they found a crystal
form in which the active site was empty and thus well-suited to fragment soaking.
In just three days the XChem researchers grew, soaked and analyzed 600 crystals.
Since then they have screened over 1000 fragments and found 7 that bind in the
active site. These will be released in the protein data bank on March 11, though
the coordinates and electron density maps can already be downloaded from XChem and viewed interactively here. An
overlay shows a large and attractive pocket with multiple opportunities for protein-ligand
interactions.
Frank sent an email on March 6 describing
this achievement to a number of researchers, and within minutes Brian Shoichet
(UCSF) said that he would be using the fragments as controls in a large library
docking screen he is doing. Just a few hours later Andrew Hopkins (Exscientia) said
that he has SPR and enzymatic assays up and running and is willing to screen
compounds sent to him. Then John Chodera (Memorial Sloan-Kettering Cancer Center)
volunteered to do free-energy calculations.
As anyone who has worked in drug
discovery, fragment-based or not, will recognize, there is still a long road ahead to turn these fragments into effective drugs. But this global team
has sprinted off the starting line. Please join them in the race if you can.
1 comment:
As part of Diamond’s effort to combat COVID-19, we are offering fragment screening expertise and infrastructure to users working on COVID-19 related targets.
In order to submit a proposal for COVID-19 related research please complete the Rapid Access Form and send a completed XChem Application Form to covid19access@diamond.ac.uk. Forms can be found here: https://www.diamond.ac.uk/covid-19/for-scientists/rapid-access.html.
Due to access and travel restrictions, experienced XChem staff will prepare samples on-site, organise unattended data collection and analyse the data using the XCE pipeline. All data will then be made available to the users and as open access through Fragalysis and the Diamond webpage.
Further details regarding crystal system requirements, available fragment libraries and screening protocols can be found on our website: https://www.diamond.ac.uk/Instruments/Mx/Fragment-Screening.html
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