Top 23 results hand-selected from a virtual fragment expansion, docking, and screening exercise. First, a set of 2.1K existing viral protease inhibitors from ChEMBL was analyzed to extract a library of 9.4K common design motifs. Reverie’s in-house fragment expansion engine was used to combinatorially place these fragments on the acetamide methyl position of fragment X0107 via a variety of simple, synthetically-accessible linkers. Results were filtered extensively for toxicity and reactivity using an in-house library of SMARTS patterns, and an RDKit cLogP cutoff of 5.0 was applied. The remaining 8.4K compounds were docked via multiple docking methods and pose-constrained to match the orientation of the crystal-bound X0107 fragment. An ensemble of scoring functions was used to select a set of 886 compounds with high predicted affinity. These compounds were manually triaged by individuals on the Reverie chemistry team to select the final set of compounds for submission. The final set includes compounds that make favorable hydrophobic interactions with His41, Met49, and Thr25, as well as some that make buried hydrogen bonds with the Thr25 sidechain and the Cys44 backbone carbonyl.
These molecules have good predicted properties to infer oral dosing, are free from structural alerts that may slow development, and are synthetically accessible from commercial building blocks so as to facilitate rapid analog synthesis, hypothesis testing and SAR follow up. Contributors: *Gabriel Grand, *Elana Simon, *Michael Bower, Bruce Clapham, Jonah Kallenbach * = equal contribution