应用人工神经网络发现锌金属蛋白酶热溶酶潜在抑制剂二苯基硅烷化合物。

IF 2.9 4区 医学 Q3 CHEMISTRY, MEDICINAL
Yudith Cañizares-Carmenate, Facundo Perez Gimenez, Roberto Diaz-Amador, Francisco Torrens, Juan A Castillo-Garit
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引用次数: 0

摘要

简介/目标:人工神经网络是非常强大的机器学习和人工智能工具,用于计算机辅助药物发现。与传统方法相比,这种方法在节省时间和金钱方面具有优势。这项工作的目的是开发机器学习人工神经网络,用于计算机辅助发现潜在的热溶酶金属蛋白酶抑制剂候选药物。方法:在这项工作中,开发了具有一般5:n:1结构的MLP(多层感知器)和RBF(径向基函数)神经网络,以发现遗传算法获得的五个分子描述符与酶的抑制之间的非线性相关性,表示为pKi。利用AMBIT Discovery软件确定了模型的适用域,并对化学合成得到的一系列二苯基硅烷的硅内活性谱进行了评价。结果:所提出的模型在两个系列中都比线性模型具有更好的拟合效果(训练集的R2 MLR = 0.71,预测集的R2 MLR = 0.72)。在MLP的情况下,发现R2值接近0.90,所有化合物都在模型的AD内。虽然rbf型模型在训练中表现出不稳定性,但我们发现了性能大于0.80的网络。然而,仅考虑了mlp型模型来预测一系列17个二苯基硅烷的活性。最后,三种化合物被确定为最有前途的热溶酶抑制剂。结论:与传统方法相比,该方法在节省时间和金钱方面具有优势。此外,研究结果表明,这三种化合物与人血管肽酶具有同源性,可用于心血管疾病的治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Discovery of Diphenylsilane Compounds as Potential Inhibitors of Zn-Metalloproteinase Thermolysin Using Artificial Neural Networks.

Introduction/objective: Artificial neural networks are very powerful machine learning and artificial intelligence tools for computer-aided drug discovery. This method offers advantages over traditional approaches related to saving time and money. The aim of this work is to develop machine-learning artificial neural networks for computer-aided discovery of potential thermolysin metalloprotease inhibitor drug candidates.

Methods: In this work, MLP (Multilayer Perceptron) and RBF (Radial Basis Function) neural networks with a general 5:n:1 architecture are developed to find a non-linear correlation between five molecular descriptors obtained by genetic algorithm, and the inhibition of the enzyme thermolysin, expressed as pKi. The AD (applicability domain) of the model was determined using the AMBIT Discovery software, and the in silico activity profile of a series of diphenylsilanes obtained by chemical synthesis was evaluated.

Results: The proposed models show a better fit than the linear model in both series (R2 MLR = 0.71 for the training set and R2 MLR = 0.72 for the prediction set). In the case of the MLP, R2 values close to 0.90 are found and all the compounds are inside the AD of the model. Although the RBF-type models show instability in training, networks with a performance greater than 0.80 are found. However, only the MLP-type models are taken into account to predict the activity of a series of 17 diphenylsilanes. Finally, three compounds are identified as the most promising thermolysin inhibitors.

Conclusion: This methodology offers advantages over traditional methods related to saving time and money. Furthermore, the results obtained suggest that the three identified compounds could be used for the treatment of cardiovascular pathologies because of their homology with human vasopeptidases.

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来源期刊
CiteScore
6.40
自引率
2.90%
发文量
186
审稿时长
3-8 weeks
期刊介绍: Current Topics in Medicinal Chemistry is a forum for the review of areas of keen and topical interest to medicinal chemists and others in the allied disciplines. Each issue is solely devoted to a specific topic, containing six to nine reviews, which provide the reader a comprehensive survey of that area. A Guest Editor who is an expert in the topic under review, will assemble each issue. The scope of Current Topics in Medicinal Chemistry will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. Medicinal chemistry is a rapidly maturing discipline. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. Current Topics in Medicinal Chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. The journal is essential for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important advances.
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