Combinatorial docking and molecular generation to navigate over 100-billion molecules for prospective ligand discovery
Тип публікації :
Препринт
Дата випуску :
11 червня 2026 р.
Автор(и) :
Jianxiang Zhang
Chao Yang
Yu Zhang
Xiao Chen
Brandon Lam
Claire Bryant
Shabareesh Pidathala
Yangzhi Wang
Yurii Moroz
Dmytro Radchenko
Assaf Alon
Chia‐Hsueh Lee
Zhe Zhang
Jiankun Lyu
eKNUTSHIR URL :
Журнал :
bioRxiv (Cold Spring Harbor Laboratory)
Цитування :
[APA 7] Jianxiang, Z., Chao, Y., Yu, Z., Xiao, C., Brandon, L., Claire, B., Shabareesh, P., Yangzhi, W., Yurii, M., Dmytro, R., Assaf, A., Chia‐Hsueh, L., Zhe, Z., & Jiankun, L. (2026). Combinatorial docking and molecular generation to navigate over 100-billion molecules for prospective ligand discovery. bioRxiv (Cold Spring Harbor Laboratory),. https://doi.org/10.64898/2026.06.07.730716
[ДСТУ] Combinatorial docking and molecular generation to navigate over 100-billion molecules for prospective ligand discovery / Z. Jianxiang та ін. bioRxiv (Cold Spring Harbor Laboratory). 2026. DOI: 10.64898/2026.06.07.730716 (дата звернення: 11.09.2026).
Abstract Commercially available make-on-demand libraries now exceed 100 billion compounds, requiring over 50 years to screen on 2,000 CPU cores using conventional docking. We present two complementary approaches to address this challenge. CombiDOCK, a combinatorial docking framework, enables exhaustive screening at the 100-billion scale within 40 days. MINT-Dock, a generative framework, accelerates navigation of this space by integrating CombiDOCK with Monte Carlo Tree Search. Benchmarked on 46 diverse targets, CombiDOCK matched full-molecule docking accuracy, and MINT-Dock achieved a 4,800-fold enrichment over random selection. Compared with prior billion-scale brute-force campaigns against σ 2 , VMAT2, and VAChT, prospective CombiDOCK screens of the 100-billion-molecule library yielded higher hit rates and more potent ligands, while MINT-Dock achieved comparable outcomes across single- and multi-target objectives with >20-fold computational cost reductions. Docking-predicted poses of the best VAChT-binding compounds were confirmed by cryo-EM structures. These methods provide exhaustive and generative paths for navigating the trillion-molecule frontier of drug discovery.
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