论文标题

豪华轿车:靶向分子产生的潜在构造论

LIMO: Latent Inceptionism for Targeted Molecule Generation

论文作者

Eckmann, Peter, Sun, Kunyang, Zhao, Bo, Feng, Mudong, Gilson, Michael K., Yu, Rose

论文摘要

在药物发现中,与靶蛋白具有高结合亲和力的药物样分子仍然是一项困难和资源密集型的任务。现有的方法主要采用强化学习,马尔可夫采样或以高斯过程为指导的深层生成模型,在产生具有高结合亲和力的分子时,通过基于计算较高的物理学方法计算出高结合亲和力。我们提出了对分子(豪华轿车)的潜在构成主义,它通过类似于造型主义的技术显着加速了分子的产生。豪华轿车采用序列的两个神经网络采用各种自动编码器生成的潜在空间和性质预测,以使分子特性的基于梯度的反相比更快。综合实验表明,豪华轿车在基准任务上具有竞争力,并且在产生具有高结合亲和力的类似药物的化合物的新任务上,效果明显超过了最先进的技术,可针对两个蛋白质靶标达到纳摩尔范围。我们通过更准确的分子动力学来证实这些基于对接的结果的绝对结合能量的计算,并表明我们产生的类似药物的化合物之一预测$ k_d $(衡量结合亲和力)为$ 6 \ cdot 10^{-14} $ M,超出了典型的早期药物,远远超出了典型的药物,远远超出了典型的药物,远远超出了典型的药物效果。目标。代码可在https://github.com/rose-stl-lab/limo上找到。

Generation of drug-like molecules with high binding affinity to target proteins remains a difficult and resource-intensive task in drug discovery. Existing approaches primarily employ reinforcement learning, Markov sampling, or deep generative models guided by Gaussian processes, which can be prohibitively slow when generating molecules with high binding affinity calculated by computationally-expensive physics-based methods. We present Latent Inceptionism on Molecules (LIMO), which significantly accelerates molecule generation with an inceptionism-like technique. LIMO employs a variational autoencoder-generated latent space and property prediction by two neural networks in sequence to enable faster gradient-based reverse-optimization of molecular properties. Comprehensive experiments show that LIMO performs competitively on benchmark tasks and markedly outperforms state-of-the-art techniques on the novel task of generating drug-like compounds with high binding affinity, reaching nanomolar range against two protein targets. We corroborate these docking-based results with more accurate molecular dynamics-based calculations of absolute binding free energy and show that one of our generated drug-like compounds has a predicted $K_D$ (a measure of binding affinity) of $6 \cdot 10^{-14}$ M against the human estrogen receptor, well beyond the affinities of typical early-stage drug candidates and most FDA-approved drugs to their respective targets. Code is available at https://github.com/Rose-STL-Lab/LIMO.

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