Employing Machine Learning Models to Predict Potential α-Glucosidase Inhibitory Plant Secondary Metabolites Targeting Type-2 Diabetes and Their In Vitro Validation.

IF 5.6 2区 化学 Q1 CHEMISTRY, MEDICINAL
Lemnaro Jamir, Hariprasad P
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引用次数: 0

Abstract

The need for new antidiabetic drugs is evident, considering the ongoing global burden of type-2 diabetes mellitus despite notable progress in drug discovery from laboratory research to clinical application. This study aimed to build machine learning (ML) models to predict potential α-glucosidase inhibitors based on the data set comprising over 537 reported plant secondary metabolite (PSM) α-glucosidase inhibitors. We assessed 35 ML models by using seven different fingerprints. The Random forest with the RDKit fingerprint was the best-performing model, with an accuracy (ACC) of 83.74% and an area under the ROC curve (AUC) of 0.803. The resulting robust ML model encompasses all reported α-glucosidase inhibitory PSMs. The model was employed to predict potential α-glucosidase inhibitors from an in-house 5810 PSM database. The model identified 965 PSMs with a prediction activity ≥0.90 for α-glucosidase inhibition. Twenty-four predicted PSMs were subjected to in vitro assay, and 13 were found to inhibit α-glucosidase with IC50 ranging from 0.63 to 7 mg/mL. Among them, seven compounds recorded IC50 values less than the standard drug acarbose and were investigated further to have optimal drug-likeness and medicinal chemistry characteristics. The ML model and in vitro experiments have identified nervonic acid as a promising α-glucosidase inhibitor. This compound should be further investigated for its potential integration into the diabetes treatment system.

利用机器学习模型预测针对 2 型糖尿病的潜在α-葡萄糖苷酶抑制性植物次生代谢物及其体外验证。
尽管药物发现从实验室研究到临床应用都取得了显著进展,但考虑到 2 型糖尿病在全球造成的持续负担,对新型抗糖尿病药物的需求显而易见。本研究旨在建立机器学习(ML)模型,根据超过 537 种已报道植物次生代谢物(PSM)α-葡萄糖苷酶抑制剂的数据集预测潜在的α-葡萄糖苷酶抑制剂。我们使用七种不同的指纹图谱评估了 35 个 ML 模型。采用 RDKit 指纹的随机森林是表现最好的模型,准确率 (ACC) 为 83.74%,ROC 曲线下面积 (AUC) 为 0.803。由此产生的稳健多变量模型涵盖了所有已报道的α-葡萄糖苷酶抑制性 PSM。该模型被用于从内部 5810 PSM 数据库中预测潜在的 α-葡萄糖苷酶抑制剂。该模型确定了 965 种对α-葡萄糖苷酶抑制作用预测活性≥0.90 的 PSM。对 24 种预测的 PSM 进行了体外试验,发现其中 13 种对 α-葡萄糖苷酶有抑制作用,其 IC50 在 0.63 至 7 毫克/毫升之间。其中,7 个化合物的 IC50 值低于标准药物阿卡波糖,经进一步研究,这些化合物具有最佳的药物相似性和药物化学特性。通过 ML 模型和体外实验,我们发现神经酸是一种很有前景的 α-葡萄糖苷酶抑制剂。应进一步研究该化合物,以便将其纳入糖尿病治疗系统。
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来源期刊
CiteScore
9.80
自引率
10.70%
发文量
529
审稿时长
1.4 months
期刊介绍: The Journal of Chemical Information and Modeling publishes papers reporting new methodology and/or important applications in the fields of chemical informatics and molecular modeling. Specific topics include the representation and computer-based searching of chemical databases, molecular modeling, computer-aided molecular design of new materials, catalysts, or ligands, development of new computational methods or efficient algorithms for chemical software, and biopharmaceutical chemistry including analyses of biological activity and other issues related to drug discovery. Astute chemists, computer scientists, and information specialists look to this monthly’s insightful research studies, programming innovations, and software reviews to keep current with advances in this integral, multidisciplinary field. As a subscriber you’ll stay abreast of database search systems, use of graph theory in chemical problems, substructure search systems, pattern recognition and clustering, analysis of chemical and physical data, molecular modeling, graphics and natural language interfaces, bibliometric and citation analysis, and synthesis design and reactions databases.
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