Fitness aligned structural modeling enables scalable virtual screening with AuroBind

• URL: http://arxiv.org/abs/2508.02137v1
• Date: Mon, 04 Aug 2025 07:34:48 GMT
• Title: Fitness aligned structural modeling enables scalable virtual screening with AuroBind
• Authors: Zhongyue Zhang, Jiahua Rao, Jie Zhong, Weiqiang Bai, Dongxue Wang, Shaobo Ning, Lifeng Qiao, Sheng Xu, Runze Ma, Will Hua, Jack Xiaoyu Chen, Odin Zhang, Wei Lu, Hanyi Feng, He Yang, Xinchao Shi, Rui Li, Wanli Ouyang, Xinzhu Ma, Jiahao Wang, Jixian Zhang, Jia Duan, Siqi Sun, Jian Zhang, Shuangjia Zheng,
• Abstract summary: We present AuroBind, a scalable virtual screening framework that fine-tunes a custom atomic-level structural model on million-scale chemogenomic data.<n>AuroBind integrates direct preference optimization, self-distillation from high-confidence complexes, and a teacher-student acceleration strategy.<n>In a prospective screen across ten disease-relevant targets, AuroBind achieved experimental hit rates of 7-69%, with top compounds reaching sub-nanomolar to picomolar potency.
• Score: 56.720030595081845
• License: http://creativecommons.org/licenses/by-sa/4.0/
• Abstract: Most human proteins remain undrugged, over 96% of human proteins remain unexploited by approved therapeutics. While structure-based virtual screening promises to expand the druggable proteome, existing methods lack atomic-level precision and fail to predict binding fitness, limiting translational impact. We present AuroBind, a scalable virtual screening framework that fine-tunes a custom atomic-level structural model on million-scale chemogenomic data. AuroBind integrates direct preference optimization, self-distillation from high-confidence complexes, and a teacher-student acceleration strategy to jointly predict ligand-bound structures and binding fitness. The proposed models outperform state-of-the-art models on structural and functional benchmarks while enabling 100,000-fold faster screening across ultra-large compound libraries. In a prospective screen across ten disease-relevant targets, AuroBind achieved experimental hit rates of 7-69%, with top compounds reaching sub-nanomolar to picomolar potency. For the orphan GPCRs GPR151 and GPR160, AuroBind identified both agonists and antagonists with success rates of 16-30%, and functional assays confirmed GPR160 modulation in liver and prostate cancer models. AuroBind offers a generalizable framework for structure-function learning and high-throughput molecular screening, bridging the gap between structure prediction and therapeutic discovery.

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