论文标题

有效的图形生成模型,用于导航超大组合合成库

An efficient graph generative model for navigating ultra-large combinatorial synthesis libraries

论文作者

Pedawi, Aryan, Gniewek, Pawel, Chang, Chaoyi, Anderson, Brandon M., Bedem, Henry van den

论文摘要

虚拟的,需求的化学图书馆通过解锁巨大的,可访问的化学空间区域,从而改变了早期药物的发现。近年来,这些图书馆的迅速增长从数百万到万亿种化合物,隐藏了未发现的,有效的打击,以实现各种治疗靶标。但是,他们迅速接近允许明确枚举的规模,对虚拟筛查提出了新的挑战。为了克服这些挑战,我们提出了组合综合文库变化自动编码器(CSLVAE)。提出的生成模型将这些库表示为一个可区分的,分层的数据库。鉴于文库的化合物,分子编码器构成了检索的查询,该查询被分子解码器用于通过首先解码其化学反应并随后解码其反应物来重建化合物。我们的设计最大程度地减少了解码器中的自动进度,从而促进了大型,有效的分子图的产生。我们的方法对超大合成库进行快速和平行的批次推断,从而在早期药物发现中实现了许多重要的应用。我们方法提出的化合物保证在库中,因此可以合成和成本效益。重要的是,CSLVAE可以编码外图化合物并搜索外部类似物。在实验中,我们证明了所提出的方法在大规模组合合成库导航中的功能。

Virtual, make-on-demand chemical libraries have transformed early-stage drug discovery by unlocking vast, synthetically accessible regions of chemical space. Recent years have witnessed rapid growth in these libraries from millions to trillions of compounds, hiding undiscovered, potent hits for a variety of therapeutic targets. However, they are quickly approaching a size beyond that which permits explicit enumeration, presenting new challenges for virtual screening. To overcome these challenges, we propose the Combinatorial Synthesis Library Variational Auto-Encoder (CSLVAE). The proposed generative model represents such libraries as a differentiable, hierarchically-organized database. Given a compound from the library, the molecular encoder constructs a query for retrieval, which is utilized by the molecular decoder to reconstruct the compound by first decoding its chemical reaction and subsequently decoding its reactants. Our design minimizes autoregression in the decoder, facilitating the generation of large, valid molecular graphs. Our method performs fast and parallel batch inference for ultra-large synthesis libraries, enabling a number of important applications in early-stage drug discovery. Compounds proposed by our method are guaranteed to be in the library, and thus synthetically and cost-effectively accessible. Importantly, CSLVAE can encode out-of-library compounds and search for in-library analogues. In experiments, we demonstrate the capabilities of the proposed method in the navigation of massive combinatorial synthesis libraries.

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