TY - JOUR
AU - Herasymenko, Oleksandra
AU - Silva, Madhushika
AU - Abu-Saleh, Abd Al-Aziz
AU - Ahmad, Ayaz
AU - Alvarado-Huayhuaz, Jesus A.
AU - Arce, Oscar E. A.
AU - Armstrong, Roly J.
AU - Arrowsmith, Cheryl
AU - Bachta, Kelly E.
AU - Beck, Harmut
AU - Berta, Denes
AU - Bieniek, Mateusz K
AU - Blay, Vincent
AU - Bolotokova, Albina
AU - Bourne, Philip E.
AU - Breznik, Marco
AU - Brown, Peter J.
AU - Campbell, Aaron D. G.
AU - Carosati, Emanuele
AU - Chau, Irene
AU - Cole, Daniel J.
AU - Cree, Ben
AU - Dehaen, Wim
AU - Denzinger, Katrin
AU - dos Santos Machado, Karina
AU - Dunn, Ian
AU - Durai, Prasannavenkatesh
AU - Edfeldt, Kristina
AU - Edwards, Aled
AU - Fayne, Darren
AU - Friston, Kallie
AU - Ghiabi, Pegah
AU - Gibson, Elisa
AU - Guenther, Judith
AU - Gunnarsson, Anders
AU - Hillisch, Alexander
AU - Houston, Douglas R.
AU - Halborg Jensen, Jan
AU - Harding, Rachel J
AU - Harris, Kate S.
AU - Hoffer, Laurent
AU - Hogner, Anders
AU - Horton, Joshua T.
AU - Houliston, Scott
AU - Hultquist, Judd F.
AU - Hutchinson, Ashley
AU - Irwin, John J.
AU - Jukič, Marko
AU - Kandwal, Shubhangi
AU - Karlova, Andrea
AU - Katis, Vittorio L.
AU - Kich, Ryan P.
AU - Kireev, Dmitri
AU - Koes, David
AU - Inniss, Nicole L.
AU - Lessel, Uta
AU - Liu, Sijie
AU - Loppnau, Peter
AU - Lu, Wei
AU - Martino, Sam Alexander
AU - McGibbon, Miles
AU - Meiler, Jens
AU - Mettu, Akhila
AU - Money-Kyrle, Sam
AU - Moretti, Rocco
AU - Moroz, Yurii S.
AU - Muvva, Charuvaka
AU - Newman, Joseph A.
AU - Obendorf, Leon
AU - Paige, Brooks
AU - Pandit, Amit
AU - Park, Keunwan
AU - Perveen, Sumera
AU - Pirie, Rachael
AU - Poda, Gennady
AU - Protopopov, Mykola
AU - Pütter, Vera
AU - Ricci, Federico
AU - Roper, Natalie J.
AU - Rosta, Edina
AU - Rzhetskaya, Margarita
AU - Sabnis, Yogesh
AU - Satchell, Karla J. F.
AU - Schmitt Kremer, Frederico
AU - Scott, Thomas
AU - Seitova, Almagul
AU - Steinmann, Casper
AU - Talagayev, Valerij
AU - Tarkhanova, Olga O.
AU - Tatum, Natalie J.
AU - Treleaven, Dakota
AU - Velasque Werhli, Adriano
AU - Walters, W. Patrick
AU - Wang, Xiaowen
AU - Wells, Jude
AU - Wells, Geoffrey
AU - Westermaier, Yvonne
AU - Wolber, Gerhard
AU - Wortmann, Lars
AU - Zhang, Jixian
AU - Zhao, Zheng
AU - Zheng, Shuangjia
AU - Schapira, Matthieu
PY - 2025
DA - June
TI - CACHE Challenge #2: Targeting the RNA Site of the SARS-CoV-2 Helicase Nsp13
JO - Journal of Chemical Information and Modeling
DO - https://doi.org/10.1021/acs.jcim.5c00535
AB - A critical assessment of computational hit finding experiments (CACHE) challenge was conducted to predict ligands for the SARS-CoV-2 Nsp13 helicase RNA binding site, a highly conserved COVID-19 target. Twenty-three participating teams comprised of computational chemists and data scientists used protein structure and data from fragment-screening paired with advanced computational and machine learning methods to each predict up to 100 inhibitory ligands. Across all teams, 1957 compounds were predicted and were subsequently procured from commercial catalogs for biophysical assays. Of these compounds, 0.7% were confirmed to bind to Nsp13 in a surface plasmon resonance assay. The six best performing computational workflows used fragment growing, active learning, or conventional virtual screening with and without complementary deep-learning scoring functions. Follow-up functional assays resulted in identification of two compound scaffolds that bound Nsp13 with a Kd below 10 µM and inhibited in vitro helicase activity. Overall, CACHE #2 participants were successful in identifying hit compound scaffolds targeting Nsp13, a central component of the coronavirus replication-transcription complex. Computational design strategies recurrently successful across the first two CACHE challenges include linking or growing docked or crystallized fragments and docking small and diverse libraries to train ultra-fast machine-learning models. The CACHE #2 competition reveals how crowd-sourcing ligand prediction efforts using a distinct array of approaches followed with critical biophysical assays can result in novel lead compounds to advance drug discovery efforts.
PB - ACS Publications
UR - https://www.research.ed.ac.uk/en/publications/39820ef6-f2e8-4770-9b71-ae471a787980
KW - Coronavirus (COVID-19)
ER