← 研踪 PaperTrailarXiv:2611.17121 · v1
Using an energy pixels approach to estimate the size a 2nd Generation DEL must be to train a high-resolution binding model
用能量像素方法估计第二代DEL的规模以训练高分辨率结合模型
首次提交 2026-11-13 01:13
版本更新 2026-11-13 01:13
雷达观测 2026-11-13 14:15
摘要
DNA-encoded libraries (DELs) are commonly used to find small-molecule binders to a target protein. But the hard part is no longer finding a hit. It is building a machine-learning model good enough to guide the medicinal chemistry that follows, one that can resolve the shift in affinity when a chemist changes a single atom. Such a model needs two things from its training data: dense sampling of the small patch of chemical space around the hit, and an adequate number of genuinely tight binders within it. A diverse naive DEL gives neither. It samples an enormous space, so any one neighborhood is covered far too thinly, and the tightest binders are rare. A model trained on that naive DEL data must extrapolate to binders tighter than any it has seen, and that is where models can fail. One way to get training data with both properties is a second-generation DEL built around the hit. We ask how complex that library must be. We treat binding as a sum of small, independent interactions, called pixels on the target and antipixels on the ligand. From the spread of affinities measured in the naive library, with no structural information and nothing yet synthesized, we estimate the complexity such a library must have to supply that dense sampling and those tight binders. The method does two useful things. It turns the number of tight binders a model needs into the number of compounds a library must contain. And it estimates the expected yield of a randomly designed second-generation DEL, so the gain from designing the library with machine learning or active learning can be measured against a baseline, without the expense of a control library as large as the experiment itself.
作者备注：11 pages, 4 figures
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v1 · 2026-11-13 01:13 · 最新观测版本
Using an energy pixels approach to estimate the size a 2nd Generation DEL must be to train a high-resolution binding model
DNA-encoded libraries (DELs) are commonly used to find small-molecule binders to a target protein. But the hard part is no longer finding a hit. It is building a machine-learning model good enough to guide the medicinal chemistry that follows, one that can resolve the shift in affinity when a chemist changes a single atom. Such a model needs two things from its training data: dense sampling of the small patch of chemical space around the hit, and an adequate number of genuinely tight binders within it. A diverse naive DEL gives neither. It samples an enormous space, so any one neighborhood is covered far too thinly, and the tightest binders are rare. A model trained on that naive DEL data must extrapolate to binders tighter than any it has seen, and that is where models can fail. One way to get training data with both properties is a second-generation DEL built around the hit. We ask how complex that library must be. We treat binding as a sum of small, independent interactions, called pixels on the target and antipixels on the ligand. From the spread of affinities measured in the naive library, with no structural information and nothing yet synthesized, we estimate the complexity such a library must have to supply that dense sampling and those tight binders. The method does two useful things. It turns the number of tight binders a model needs into the number of compounds a library must contain. And it estimates the expected yield of a randomly designed second-generation DEL, so the gain from designing the library with machine learning or active learning can be measured against a baseline, without the expense of a control library as large as the experiment itself.
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