We’re launching the third weekly compound prioritization sprint for the COVID Moonshot! This sprint focuses on our benzotriazole lead series. These compounds came about from a previous series of potent inhibitors developed for SARS-CoV-1 (the virus that causes SARS) Mpro that are unfortunately inactive against SARS-CoV-2. However, these compounds still bind—if weakly—and can likely be optimized to adapt them to the modified active site of SARS-CoV-2 Mpro. Compounds like ALP-POS-c59291d4-2 are examples of this promising lead series.
UPDATE: Sprint 3 is live as of Sat 29 Aug 05:03:22 UTC! We’ve managed to fix the issues with large RUN-to-RUN variation, and base credit is now inline with other non-134xx projects now that we have solved the RUN variation issues. Stay tuned for a blog post on the conclusions from Sprint 2!
By making use of a synthetic route that allows installation of substituents at two different sites by selecting among available starting materials, we can generate a large variety of different substituents that access the P1′ and P2/P4 pockets.
The third compound prioritization sprint, starting today (Sun 22 Aug), examines a set of 504 potential compounds we could synthesize to tune the P1′ and P2/P4 pocket engagement for this lead series as we try to adapt this potent SARS-CoV-1 inhibitor to the modified features in SARS-CoV-2 Mpro. We’re using two separate X-ray structures as reference structures, doubling the number of calculations, but with your help, we can complete this sprint by Friday to quickly get new compounds off for synthesis.
Update on Sprint 2
The second weekly compound prioritization sprint for the COVID Moonshot—an open science COVID-19 drug discovery project—is wrapping up in just a few hours. As of Sunday afternoon, over 300,000 amazing Folding@home volunteers have completed a total of 1.5 million work units evaluating new small molecules bound to the SARS-CoV-2 main viral protease (Mpro). This represents over 6 milliseconds of molecular dynamics simulation data generated in just the past week, for just this sprint! I can’t begin to express just how incredible this is, and how excited I am about some significant performance improvements coming up that will accelerate our progress even further. More on that soon!
While we only made it about halfway through the current compound prioritization sprint, this allowed us to evaluate over 3500 potential compounds to see which we should send off to our partners at Enamine for synthesis, who have a number of chemists already working hard on making compounds from the previous sprints.
Like the first sprint, we were surprised at how few compounds show significant potency increases—you can see the small fraction of compounds that have relative free energies to the left of zero—only 51 / 800 (6%) in the quick analysis that was performed earlier this week showed the potential for improvement over the reference 3-aminopyridine lead compound, and 17/800 (2.8%) showed >1 kcal/mol improvement. We’re still wrangling the statistics for the end of the sprint, and will update you all shortly.
Superstar computational chemist Hannah Bruce Macdonald and ninja data scientist Matt Wittman (who is helping us out for a couple of months thanks to a generous emergency supplement from the NSF) have automated a huge amount of our analysis pipeline over the past week, which will allow us to start pushing public progress reports for which compounds are in the lea hourly in the next couple of weeks.
Update on Sprint 1 results
We are eagerly anticipating the results from these previous sprints, which are expected in 2-3 weeks as synthesized compounds make their way to the Diamond Light Source for X-ray crystallography and the London lab at the Weizmann Institute for affinity measurements. The sets of compounds selected for synthesis have been submitted as separate entries to the Moonshot site based on the chemical synthesis reactions they utilize:
You can track the progress of all compounds through the synthesis and assay stages with the COVID Moonshot Compound Tracker page:
Help us help you
The COVID Moonshot is an open science, patent free collaboration to develop an inexpensive therapeutic for COVID-19. We and other laboratories are mostly funding the synthesis of new compounds out of our own lab budget and the a small grant from the National Science Foundation (NSF CHE 2033426, which provides ~$60,000 for synthesis). While we are actively working to recruit additional federal funding, you can help us speed up progress toward a new COVID-19 therapy by supporting our fundraiser to help fund the synthesis of new compounds: https://www.gofundme.com/f/covidmoonshot