tetano
Editor, Senior Moderator
J Chem Inf Model
. 2026 Jan 21.
doi: 10.1021/acs.jcim.5c02441. Online ahead of print.
CACHE Challenge #3: Targeting the Nsp3 Macrodomain of SARS-CoV-2
Oleksandra Herasymenko[SUP] 1 [/SUP], Madhushika Silva[SUP] 1 [/SUP], Galen J Correy[SUP] 2 [/SUP], Abd Al-Aziz A Abu-Saleh[SUP] 3 4 [/SUP], Suzanne Ackloo[SUP] 1 [/SUP], Cheryl Arrowsmith[SUP] 1 5 6 [/SUP], Alan Ashworth[SUP] 7 [/SUP], Fuqiang Ban[SUP] 8 [/SUP], Hartmut Beck[SUP] 9 [/SUP], Kevin P Bishop[SUP] 10 11 [/SUP], Hugo J Bohórquez[SUP] 10 11 [/SUP], Albina Bolotokova[SUP] 1 [/SUP], Marko Breznik[SUP] 12 [/SUP], Irene Chau[SUP] 1 [/SUP], Yu Chen[SUP] 12 [/SUP], Artem Cherkasov[SUP] 13 [/SUP], Wim Dehaen[SUP] 14 15 [/SUP], Dennis Della Corte[SUP] 16 [/SUP], Katrin Denzinger[SUP] 12 [/SUP], Niklas P Doering[SUP] 12 [/SUP], Kristina Edfeldt[SUP] 17 [/SUP], Aled Edwards[SUP] 1 [/SUP], Darren Fayne[SUP] 18 19 [/SUP], Francesco Gentile[SUP] 20 21 [/SUP], Elisa Gibson[SUP] 1 [/SUP], Ozan Gokdemir[SUP] 22 23 [/SUP], Anders Gunnarsson[SUP] 24 [/SUP], Judith Günther[SUP] 25 [/SUP], John J Irwin[SUP] 26 [/SUP], Jan Halborg Jensen[SUP] 27 [/SUP], Rachel J Harding[SUP] 1 6 28 29 [/SUP], Alexander Hillisch[SUP] 30 [/SUP], Laurent Hoffer[SUP] 10 11 [/SUP], Anders Hogner[SUP] 31 [/SUP], Ashley Hutchinson[SUP] 1 [/SUP], Shubhangi Kandwal[SUP] 18 19 32 33 [/SUP], Andrea Karlova[SUP] 34 [/SUP], Kushal Koirala[SUP] 35 [/SUP], Sergei Kotelnikov[SUP] 36 [/SUP], Dima Kozakov[SUP] 36 [/SUP], Juyong Lee[SUP] 37 38 39 [/SUP], Soowon Lee[SUP] 38 [/SUP], Uta Lessel[SUP] 40 [/SUP], Sijie Liu[SUP] 12 [/SUP], Xuefeng Liu[SUP] 22 23 [/SUP], Peter Loppnau[SUP] 1 [/SUP], Jens Meiler[SUP] 41 42 43 [/SUP], Rocco Moretti[SUP] 44 [/SUP], Yurii S Moroz[SUP] 45 [/SUP], Charuvaka Muvva[SUP] 46 [/SUP], Tudor I Oprea[SUP] 47 [/SUP], Brooks Paige[SUP] 48 [/SUP], Amit Pandit[SUP] 12 49 [/SUP], Keunwan Park[SUP] 46 [/SUP], Gennady Poda[SUP] 10 11 28 [/SUP], Mykola V Protopopov[SUP] 45 [/SUP], Vera Pütter[SUP] 50 [/SUP], Rahul Ravichandran[SUP] 20 [/SUP], Didier Rognan[SUP] 51 [/SUP], Edina Rosta[SUP] 52 [/SUP], Yogesh Sabnis[SUP] 53 [/SUP], Thomas Scott[SUP] 44 [/SUP], Almagul Seitova[SUP] 1 [/SUP], Purshotam Sharma[SUP] 3 4 [/SUP], François Sindt[SUP] 51 [/SUP], Minghu Song[SUP] 54 [/SUP], Casper Steinmann[SUP] 55 [/SUP], Rick Stevens[SUP] 22 23 [/SUP], Valerij Talagayev[SUP] 12 [/SUP], Valentyna V Tararina[SUP] 56 [/SUP], Olga Tarkhanova[SUP] 42 [/SUP], Damon Tingey[SUP] 16 [/SUP], John F Trant[SUP] 3 4 57 [/SUP], Dakota Treleaven[SUP] 58 [/SUP], Alexander Tropsha[SUP] 35 [/SUP], Patrick Walters[SUP] 59 [/SUP], Jude Wells[SUP] 34 [/SUP], Yvonne Westermaier[SUP] 60 [/SUP], Gerhard Wolber[SUP] 12 [/SUP], Lars Wortmann[SUP] 61 [/SUP], Shuangjia Zheng[SUP] 62 [/SUP], James S Fraser[SUP] 2 [/SUP], Matthieu Schapira[SUP] 1 6 29 [/SUP]
Affiliations
The third Critical Assessment of Computational Hit-finding Experiments (CACHE) challenged computational teams to identify chemically novel ligands targeting the macrodomain 1 of SARS-CoV-2 Nsp3, a promising coronavirus drug target. Twenty-three groups deployed diverse design strategies to collectively select 1739 ligand candidates. While over 85% of the designed molecules were chemically novel, the best experimentally confirmed hits were structurally similar to previously published compounds. Confirming a trend observed in CACHE #1 and #2, two of the best-performing workflows used compounds selected by physics-based computational screening methods to train machine learning models able to rapidly screen large chemical libraries, while four others used exclusively physics-based approaches. Three pharmacophore searches and one fragment growing strategy were also part of the seven winning workflows. While active molecules discovered by CACHE #3 participants largely mimicked the adenine ring of the endogenous substrate, ADP-ribose, preserving the canonical chemotype commonly observed in previously reported Nsp3-Mac1 ligands, they still provide novel structure-activity relationship insights that may inform the development of future antivirals. Collectively, these results show that multiple molecular design strategies can efficiently converge on similar potent molecules.
. 2026 Jan 21.
doi: 10.1021/acs.jcim.5c02441. Online ahead of print.
CACHE Challenge #3: Targeting the Nsp3 Macrodomain of SARS-CoV-2
Oleksandra Herasymenko[SUP] 1 [/SUP], Madhushika Silva[SUP] 1 [/SUP], Galen J Correy[SUP] 2 [/SUP], Abd Al-Aziz A Abu-Saleh[SUP] 3 4 [/SUP], Suzanne Ackloo[SUP] 1 [/SUP], Cheryl Arrowsmith[SUP] 1 5 6 [/SUP], Alan Ashworth[SUP] 7 [/SUP], Fuqiang Ban[SUP] 8 [/SUP], Hartmut Beck[SUP] 9 [/SUP], Kevin P Bishop[SUP] 10 11 [/SUP], Hugo J Bohórquez[SUP] 10 11 [/SUP], Albina Bolotokova[SUP] 1 [/SUP], Marko Breznik[SUP] 12 [/SUP], Irene Chau[SUP] 1 [/SUP], Yu Chen[SUP] 12 [/SUP], Artem Cherkasov[SUP] 13 [/SUP], Wim Dehaen[SUP] 14 15 [/SUP], Dennis Della Corte[SUP] 16 [/SUP], Katrin Denzinger[SUP] 12 [/SUP], Niklas P Doering[SUP] 12 [/SUP], Kristina Edfeldt[SUP] 17 [/SUP], Aled Edwards[SUP] 1 [/SUP], Darren Fayne[SUP] 18 19 [/SUP], Francesco Gentile[SUP] 20 21 [/SUP], Elisa Gibson[SUP] 1 [/SUP], Ozan Gokdemir[SUP] 22 23 [/SUP], Anders Gunnarsson[SUP] 24 [/SUP], Judith Günther[SUP] 25 [/SUP], John J Irwin[SUP] 26 [/SUP], Jan Halborg Jensen[SUP] 27 [/SUP], Rachel J Harding[SUP] 1 6 28 29 [/SUP], Alexander Hillisch[SUP] 30 [/SUP], Laurent Hoffer[SUP] 10 11 [/SUP], Anders Hogner[SUP] 31 [/SUP], Ashley Hutchinson[SUP] 1 [/SUP], Shubhangi Kandwal[SUP] 18 19 32 33 [/SUP], Andrea Karlova[SUP] 34 [/SUP], Kushal Koirala[SUP] 35 [/SUP], Sergei Kotelnikov[SUP] 36 [/SUP], Dima Kozakov[SUP] 36 [/SUP], Juyong Lee[SUP] 37 38 39 [/SUP], Soowon Lee[SUP] 38 [/SUP], Uta Lessel[SUP] 40 [/SUP], Sijie Liu[SUP] 12 [/SUP], Xuefeng Liu[SUP] 22 23 [/SUP], Peter Loppnau[SUP] 1 [/SUP], Jens Meiler[SUP] 41 42 43 [/SUP], Rocco Moretti[SUP] 44 [/SUP], Yurii S Moroz[SUP] 45 [/SUP], Charuvaka Muvva[SUP] 46 [/SUP], Tudor I Oprea[SUP] 47 [/SUP], Brooks Paige[SUP] 48 [/SUP], Amit Pandit[SUP] 12 49 [/SUP], Keunwan Park[SUP] 46 [/SUP], Gennady Poda[SUP] 10 11 28 [/SUP], Mykola V Protopopov[SUP] 45 [/SUP], Vera Pütter[SUP] 50 [/SUP], Rahul Ravichandran[SUP] 20 [/SUP], Didier Rognan[SUP] 51 [/SUP], Edina Rosta[SUP] 52 [/SUP], Yogesh Sabnis[SUP] 53 [/SUP], Thomas Scott[SUP] 44 [/SUP], Almagul Seitova[SUP] 1 [/SUP], Purshotam Sharma[SUP] 3 4 [/SUP], François Sindt[SUP] 51 [/SUP], Minghu Song[SUP] 54 [/SUP], Casper Steinmann[SUP] 55 [/SUP], Rick Stevens[SUP] 22 23 [/SUP], Valerij Talagayev[SUP] 12 [/SUP], Valentyna V Tararina[SUP] 56 [/SUP], Olga Tarkhanova[SUP] 42 [/SUP], Damon Tingey[SUP] 16 [/SUP], John F Trant[SUP] 3 4 57 [/SUP], Dakota Treleaven[SUP] 58 [/SUP], Alexander Tropsha[SUP] 35 [/SUP], Patrick Walters[SUP] 59 [/SUP], Jude Wells[SUP] 34 [/SUP], Yvonne Westermaier[SUP] 60 [/SUP], Gerhard Wolber[SUP] 12 [/SUP], Lars Wortmann[SUP] 61 [/SUP], Shuangjia Zheng[SUP] 62 [/SUP], James S Fraser[SUP] 2 [/SUP], Matthieu Schapira[SUP] 1 6 29 [/SUP]
Affiliations
- PMID: 41565251
- DOI: 10.1021/acs.jcim.5c02441
The third Critical Assessment of Computational Hit-finding Experiments (CACHE) challenged computational teams to identify chemically novel ligands targeting the macrodomain 1 of SARS-CoV-2 Nsp3, a promising coronavirus drug target. Twenty-three groups deployed diverse design strategies to collectively select 1739 ligand candidates. While over 85% of the designed molecules were chemically novel, the best experimentally confirmed hits were structurally similar to previously published compounds. Confirming a trend observed in CACHE #1 and #2, two of the best-performing workflows used compounds selected by physics-based computational screening methods to train machine learning models able to rapidly screen large chemical libraries, while four others used exclusively physics-based approaches. Three pharmacophore searches and one fragment growing strategy were also part of the seven winning workflows. While active molecules discovered by CACHE #3 participants largely mimicked the adenine ring of the endogenous substrate, ADP-ribose, preserving the canonical chemotype commonly observed in previously reported Nsp3-Mac1 ligands, they still provide novel structure-activity relationship insights that may inform the development of future antivirals. Collectively, these results show that multiple molecular design strategies can efficiently converge on similar potent molecules.