论文标题

使用基于图的深层生成模型的从头设计

De novo PROTAC design using graph-based deep generative models

论文作者

Nori, Divya, Coley, Connor W., Mercado, Rocío

论文摘要

储层计算是预测湍流的有力工具,其简单的架构具有处理大型系统的计算效率。然而,其实现通常需要完整的状态向量测量和系统非线性知识。我们使用非线性投影函数将系统测量扩展到高维空间,然后将其输入到储层中以获得预测。我们展示了这种储层计算网络在时空混沌系统上的应用,该系统模拟了湍流的若干特征。我们表明,使用径向基函数作为非线性投影器,即使只有部分观测并且不知道控制方程,也能稳健地捕捉复杂的系统非线性。最后,我们表明,当测量稀疏、不完整且带有噪声,甚至控制方程变得不准确时,我们的网络仍然可以产生相当准确的预测,从而为实际湍流系统的无模型预测铺平了道路。

PROteolysis TArgeting Chimeras (PROTACs) are an emerging therapeutic modality for degrading a protein of interest (POI) by marking it for degradation by the proteasome. Recent developments in artificial intelligence (AI) suggest that deep generative models can assist with the de novo design of molecules with desired properties, and their application to PROTAC design remains largely unexplored. We show that a graph-based generative model can be used to propose novel PROTAC-like structures from empty graphs. Our model can be guided towards the generation of large molecules (30--140 heavy atoms) predicted to degrade a POI through policy-gradient reinforcement learning (RL). Rewards during RL are applied using a boosted tree surrogate model that predicts a molecule's degradation potential for each POI. Using this approach, we steer the generative model towards compounds with higher likelihoods of predicted degradation activity. Despite being trained on sparse public data, the generative model proposes molecules with substructures found in known degraders. After fine-tuning, predicted activity against a challenging POI increases from 50% to >80% with near-perfect chemical validity for sampled compounds, suggesting this is a promising approach for the optimization of large, PROTAC-like molecules for targeted protein degradation.

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