GPCRLigNet: rapid screening for GPCR active ligands using machine learning

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jacob M Remington, Kyle T McKay, Noah B Beckage, Jonathon B Ferrell, Severin T. Schneebeli, Jianing Li
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引用次数: 1

Abstract

Molecules with bioactivity towards G protein-coupled receptors represent a subset of the vast space of small drug-like molecules. Here, we compare machine learning models, including dilated graph convolutional networks, that conduct binary classification to quickly identify molecules with activity towards G protein-coupled receptors. The models are trained and validated using a large set of over 600,000 active, inactive, and decoy compounds. The best performing machine learning model, dubbed GPCRLigNet, was a surprisingly simple feedforward dense neural network mapping from Morgan fingerprints to activity. Incorporation of GPCRLigNet into a high-throughput virtual screening workflow is demonstrated with molecular docking towards a particular G protein-coupled receptor, the pituitary adenylate cyclase-activating polypeptide receptor type 1. Through rigorous comparison of docking scores for molecules selected with and without using GPCRLigNet, we demonstrate an enrichment of potentially potent molecules using GPCRLigNet. This work provides a proof of principle that GPCRLigNet can effectively hone the chemical search space towards ligands with G protein-coupled receptor activity.

Abstract Image

GPCRLigNet:利用机器学习快速筛选GPCR活性配体
对G蛋白偶联受体具有生物活性的分子代表了大量小药物样分子的一个子集。在这里,我们比较了机器学习模型,包括扩展图卷积网络,进行二元分类,以快速识别对G蛋白偶联受体有活性的分子。这些模型使用超过60万种活性、非活性和诱饵化合物进行训练和验证。表现最好的机器学习模型被称为GPCRLigNet,它是一个非常简单的前馈密集神经网络,从摩根指纹映射到活动。通过与特定G蛋白偶联受体(垂体腺苷酸环化酶激活多肽受体1型)的分子对接,证明了GPCRLigNet与高通量虚拟筛选工作流程的结合。通过严格比较使用和不使用GPCRLigNet选择的分子的对接分数,我们证明了使用GPCRLigNet可以富集潜在的有效分子。这项工作提供了一个原理证明,GPCRLigNet可以有效地扩大对具有G蛋白偶联受体活性的配体的化学搜索空间。
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来源期刊
Journal of Computer-Aided Molecular Design
Journal of Computer-Aided Molecular Design 生物-计算机:跨学科应用
CiteScore
8.00
自引率
8.60%
发文量
56
审稿时长
3 months
期刊介绍: The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - theoretical chemistry; - computational chemistry; - computer and molecular graphics; - molecular modeling; - protein engineering; - drug design; - expert systems; - general structure-property relationships; - molecular dynamics; - chemical database development and usage.
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