CACHE Challenge #1: targeting the WDR domain of LRRK2, a Parkinson’s Disease associated protein
Authors: Li Fengling , Ackloo Suzanne , Arrowsmith Cheryl H. , Ban Fuqiang , Barden Christopher J. , Beck Hartmut , Beránek Jan , Berenger Francois , Bolotokova Albina , Bret Guillaume , Breznik Marko , Carosati Emanuele , Chau Irene , Chen Yu , Cherkasov Artem , Della Corte Dennis , Denzinger Katrin , Dong Aiping , Draga Sorin , Dunn Ian , Edfeldt Kristina , Edwards Aled , Eguida Merveille , Eisenhuth Paul , Friedrich Lukas , Fuerll Alexander , Gardiner Spencer S , Gentile Francesco , Ghiabi Pegah , Gibson Elisa , Glavatskikh Marta , Gorgulla Christoph , Guenther Judith , Gunnarsson Anders , Gusev Filipp , Gutkin Evgeny , Halabelian Levon , Harding Rachel J. , Hillisch Alexander , Hoffer Laurent , Hogner Anders , Houliston Scott , Irwin John J , Isayev Olexandr , Ivanova Aleksandra , Jarrett Austin J , Jensen Jan H. , Kireev Dmitri , Kleber Julian , Koby S. Benjamin , Koes David , Kumar Ashutosh , Kurnikova Maria G. , Kutlushina Alina , Lessel Uta , Liessmann Fabian , Liu Sijie , Lu Wei , Meiler Jens , Mettu Akhila , Minibaeva Guzel , Moretti Rocco , Morris Connor J , Narangoda Chamali , Noonan Theresa , Obendorf Leon , Pach Szymon , Pandit Amit , Perveen Sumera , Poda Gennady , Polishchuk Pavel , Puls Kristina , Pütter Vera , Rognan Didier , Roskams-Edris Dylan , Schindler Christina , Sindt François , Spiwok Vojtěch , Steinmann Casper , Stevens Rick L. , Talagayev Valerij , Tingey Damon , Vu Oanh , Walters W. Patrick , Wang Xiaowen , Wang Zhenyu , Wolber Gerhard , Wolf Clemens Alexander , Wortmann Lars , Zeng Hong , Zepeda Carlos A. , Zhang Kam Y. J. , Zhang Jixian , Zheng Shuangjia , Schapira Matthieu 
Published: July 2024

ABSTRACTThe CACHE challenges are a series of prospective benchmarking exercises meant to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE #1 challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson’s disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods. Seventy-three of the 1955 procured molecules bound LRRK2 in an SPR assay with KDlower than 150 μM and were advanced to a hit expansion phase where computational teams each selected up to 50 analogs each. Binding was observed in two orthogonal assays with affinities ranging from 18 to 140 μM for seven chemically diverse series. The seven successful computational workflows varied in their screening strategies and techniques. Three used molecular dynamics to produce a conformational ensemble of the targeted site, three included a fragment docking step, three implemented a generative design strategy and five used one or more deep learning steps. CACHE #1 reflects a highly exploratory phase in computational drug design where participants sometimes adopted strikingly diverging screening strategies. Machine-learning accelerated methods achieved similar results to brute force (e.g. exhaustive) docking. First-in-class, experimentally confirmed compounds were rare and weakly potent, indicating that recent advances are not sufficient to effectively address challenging targets.