论文标题

通过深层生成基础模型的加速抑制剂发现:SARS-COV-2药物目标的验证

Accelerating Inhibitor Discovery With A Deep Generative Foundation Model: Validation for SARS-CoV-2 Drug Targets

论文作者

Chenthamarakshan, Vijil, Hoffman, Samuel C., Owen, C. David, Lukacik, Petra, Strain-Damerell, Claire, Fearon, Daren, Malla, Tika R., Tumber, Anthony, Schofield, Christopher J., Duyvesteyn, Helen M. E., Dejnirattisai, Wanwisa, Carrique, Loic, Walter, Thomas S., Screaton, Gavin R., Matviiuk, Tetiana, Mojsilovic, Aleksandra, Crain, Jason, Walsh, Martin A., Stuart, David I., Das, Payel

论文摘要

新型抑制剂分子用于新兴药物目标蛋白被广泛认为是一个具有挑战性的反设计问题:详尽的化学搜索空间的详尽探索是不切实际的,尤其是当目标结构或活性分子未知时。在这里,我们在实验中验证了经过蛋白质序列,小分子及其相互作用的深层生成框架的广泛效用 - 对任何特定目标都是公正的。作为示威者,我们考虑了两个不同和相关的SARS-COV-2靶标:主要蛋白酶和尖峰蛋白(受体结合结构域,RBD)。为了执行新型抑制剂分子的目标感知设计,对生成基础模型进行了蛋白质序列条件的采样。尽管仅使用目标序列信息,并且不使用生成模型的任何目标特异性适应,但在体外实验中观察到了微摩尔级抑制作用,对于每个目标中仅合成的四个合成的两个候选者中的两个候选者。最有效的尖峰RBD抑制剂还表现出对活病毒中和测定中几种变体的活性。因此,这些结果表明,即使在目标结构和粘合剂信息都没有可用的情况下,即使在最普遍的情况下,即使在最普遍的情况下,一个可加速的HIT发现的单一,可部署的生成基础模型也是有效而有效的。

The discovery of novel inhibitor molecules for emerging drug-target proteins is widely acknowledged as a challenging inverse design problem: Exhaustive exploration of the vast chemical search space is impractical, especially when the target structure or active molecules are unknown. Here we validate experimentally the broad utility of a deep generative framework trained at-scale on protein sequences, small molecules, and their mutual interactions -- that is unbiased toward any specific target. As demonstrators, we consider two dissimilar and relevant SARS-CoV-2 targets: the main protease and the spike protein (receptor binding domain, RBD). To perform target-aware design of novel inhibitor molecules, a protein sequence-conditioned sampling on the generative foundation model is performed. Despite using only the target sequence information, and without performing any target-specific adaptation of the generative model, micromolar-level inhibition was observed in in vitro experiments for two candidates out of only four synthesized for each target. The most potent spike RBD inhibitor also exhibited activity against several variants in live virus neutralization assays. These results therefore establish that a single, broadly deployable generative foundation model for accelerated hit discovery is effective and efficient, even in the most general case where neither target structure nor binder information is available.

扫码加入交流群

加入微信交流群

微信交流群二维码

扫码加入学术交流群,获取更多资源