Yudith Cañizares-Carmenate, Facundo Perez Gimenez, Roberto Diaz-Amador, Francisco Torrens, Juan A Castillo-Garit
{"title":"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。","authors":"Yudith Cañizares-Carmenate, Facundo Perez Gimenez, Roberto Diaz-Amador, Francisco Torrens, Juan A Castillo-Garit","doi":"10.2174/0115680266369656250428053942","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction/objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of Diphenylsilane Compounds as Potential Inhibitors of Zn-Metalloproteinase Thermolysin Using Artificial Neural Networks.\",\"authors\":\"Yudith Cañizares-Carmenate, Facundo Perez Gimenez, Roberto Diaz-Amador, Francisco Torrens, Juan A Castillo-Garit\",\"doi\":\"10.2174/0115680266369656250428053942\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction/objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":11076,\"journal\":{\"name\":\"Current topics in medicinal chemistry\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2025-05-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current topics in medicinal chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2174/0115680266369656250428053942\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current topics in medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/0115680266369656250428053942","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
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.
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.