29 March 2020

A crowdsourcing call to action: FBLD vs SARS-CoV-2 Protease

In less than a week the number of cases of COVID-19 worldwide has more than doubled, beyond 720,000, as have the number of deaths, to more than 34,000. For those of us in drug discovery but not on the front lines of clinical care, it is frustrating to watch these numbers climb relentlessly while doing nothing to help other than physical distancing. The temporary closure of so many labs accentuates this feeling.

In early March we highlighted an effort by Dave Stuart, Martin Walsh, Frank von Delft, and others at the Diamond Light Source to screen fragments against crystals of the main protease (MPro) of SARS-CoV-2. The enzyme is a cysteine protease, ideal for covalent fragment screening, and indeed Nir London and coworkers at the Weizmann Institute used intact protein mass-spectrometry to pre-screen 993 fragments. In total, these combined efforts yielded crystal structures of 44 hits bound covalently to the active-site cysteine, 22 non-covalent hits in the active site, and 2 non-covalent hits at the protein dimer interface. Full details and structures can be found here.

In our previous post we showed an overlay of the seven fragments that had been released at the time showing multiple high-quality interactions with the protein. You can look at them all interactively here, and some of the chemical structures are shown below.

This is where crowdsourcing comes in. A group called PostEra (corrected: part of a consortium called COVID MoonShot), consisting of academic and industrial researchers around the world, is trying to use these data and more to develop drugs against SARS-CoV-2. Everyone is invited to contribute, from first year graduate students through industry veterans and emeritus professors.

Do you have ideas how you might grow or merge some of the fragments? If so, you can propose structures, and those that pass a series of filters including synthetic accessibility and toxicity predictions will be synthesized at Enamine and tested at various laboratories (including yours, if you’re interested). We’ve previously highlighted Enamine’s “make on demand” model, which has turnaround times of just a few weeks. At least a couple computational companies, including BioSolveIT and Nanome, are offering free access to their platforms to help you design molecules. Already more than 350 molecule ideas have been submitted.

A cynic could say that these efforts are misguided given the slow pace of drug discovery. Vemurafenib, the first fragment-based drug approved, took six years from the start of the program to approval, and this is lightening speed. However, as Derek Lowe observed, all of the drugs currently being clinically tested against COVID-19 were originally developed for other indications. Stephen Burley suggested recently in Nature that we probably would already have drugs against COVID-19 had we spent more effort fighting SARS.

Hopefully we will have a vaccine long before any drugs coming out of this effort enter the clinic. But there will be a SARS-CoV-3, and a SARS-CoV-4. Having more drugs in our pipeline may prevent those from killing so many people.


Byron DeLaBarre said...

Exactly! Prepare for the next one. Protease is not the only covxx target worth pursuing, but it is tractable with these methods. We need to see this work through to a drug.

Manwithglasses said...

I can't tell if you covered this in your post or not: each fragment would seem a starting point to use to select a much smaller subset from the vast libraries available for in silico docking. If so, the time and computational power required would seem greatly reduced.