Submission Details
Molecule(s):
CCNc1ncc(C#N)cc1CCc1cccc(C(N)=O)c1
CCNc1ncc(C#N)cc1NCc1ccc2[nH]ncc2c1
CCNc1ncc(C#N)cc1OCc1ccc2[nH]ncc2c1
CCNc1ncc(C#N)cc1N(C)Cc1ccc2[nH]ncc2c1
CCNc1cc(NCc2ccc3[nH]ncc3c2)c(C#N)cn1
CCNc1ncc(C#N)cc1NCCc1ccc2cn[nH]c2c1
CCNc1ncc(C#N)cc1C(=O)NCc1ccc2cn[nH]c2c1
CCNc1ncc(C#N)cc1Oc1nc(-c2ccc(F)cc2)cs1
CCNc1ncc(C#N)cc1CNS(=O)(=O)c1ccc(F)cc1
CCNc1ncc(C#N)cc1N(C)c1cn(C(C)=O)c2ccccc12
CCNc1ncc(C#N)cc1N(C)c1ccc2nc(C)sc2c1
CCNc1ncc(C#N)cc1OCc1ccc2[nH]ccc2c1
CCNc1ncc(C#N)cc1Nc1ccc2[nH]ccc2c1
CCNc1ncc(C#N)cc1Oc1c(C)n(C)n(-c2ccccc2)c1=O
CCNc1ncc(C#N)cc1CNc1nc2ccccc2o1
CCNc1ncc(C#N)cc1N(C)c1nc(-c2ccccc2)cs1
CCNc1ncc(C#N)cc1N(C)c1ccc(S(N)(=O)=O)cc1
CCNc1ncc(C#N)cc1NCc1c[nH]c2ccccc12
GAB-REV-df64cf17-19
Duplicate of:
MAK-UNK-516d8086-3
CCNc1ncc(C#N)cc1Cc1ccc2c(c1)C(=O)NC2
CCNc1ncc(C#N)cc1NCc1ccc2c(c1)C(=O)NC2
CCNc1ncc(C#N)cc1CCc1cnc2ccccc2n1
CCNc1ncc(C#N)cc1NCCc1ccc2ncoc2c1
Design Rationale:
Top 22 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 3- and 4- positions of the 5-cyanopyridine of fragment X0305 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 19.4K compounds were docked via multiple docking methods and pose-constrained to match the orientation of the crystal-bound X0305 fragment. An ensemble of scoring functions was used to select a set of 479 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 Phe140, His163, Thr25, Thr45, Met145, His41, and Asn142.
Other Notes:
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)