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.