论文标题

SARS-COV-2上的Paccmann $^{rl} $:设计有条件生成模型的抗病毒药

PaccMann$^{RL}$ on SARS-CoV-2: Designing antiviral candidates with conditional generative models

论文作者

Born, Jannis, Manica, Matteo, Cadow, Joris, Markert, Greta, Mill, Nil Adell, Filipavicius, Modestas, Martínez, María Rodríguez

论文摘要

随着COVID-19成为全球大流行的快速发展,全球科学家正在拼命寻找有效的抗病毒治疗剂。桥接系统生物学和药物发现,我们为针对给定蛋白质靶标量身定制的抗病毒候选药物的从头设计框架提出了一个深度学习框架。首先,我们训练一种多模式的配体 - 蛋白结合亲和力模型,以预测抗病毒化合物对靶蛋白的亲和力,并将该模型与药理毒性预测因子相结合。利用这种多目标作为条件分子发生器的奖励函数(由两个VAE组成),我们展示了一个框架,该框架将化学空间导航到具有更多抗病毒分子的区域。具体而言,我们通过对41个与SARS-COV-2相关靶蛋白进行剩余的杂交验证来探索针对看不见的蛋白质靶标的配体的具有挑战性的环境。使用深RL,证明在41例中,有35例中,这一产生偏向于采样更多的结合配体,平均增加了83%,与无偏见的VAE相比。我们对潜在的包膜蛋白抑制剂进行了案例研究,并对最佳产生的分子进行了合成可及性评估,该评估类似于对潜在的SARS-COV-2抑制剂的快速视野评估的可行路线图。

With the fast development of COVID-19 into a global pandemic, scientists around the globe are desperately searching for effective antiviral therapeutic agents. Bridging systems biology and drug discovery, we propose a deep learning framework for conditional de novo design of antiviral candidate drugs tailored against given protein targets. First, we train a multimodal ligand--protein binding affinity model on predicting affinities of antiviral compounds to target proteins and couple this model with pharmacological toxicity predictors. Exploiting this multi-objective as a reward function of a conditional molecular generator (consisting of two VAEs), we showcase a framework that navigates the chemical space toward regions with more antiviral molecules. Specifically, we explore a challenging setting of generating ligands against unseen protein targets by performing a leave-one-out-cross-validation on 41 SARS-CoV-2-related target proteins. Using deep RL, it is demonstrated that in 35 out of 41 cases, the generation is biased towards sampling more binding ligands, with an average increase of 83% comparing to an unbiased VAE. We present a case-study on a potential Envelope-protein inhibitor and perform a synthetic accessibility assessment of the best generated molecules is performed that resembles a viable roadmap towards a rapid in-vitro evaluation of potential SARS-CoV-2 inhibitors.

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