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针对 SARS-CoV-2 Mpro 的潜在抑制剂的从头设计。

De Novo design of potential inhibitors against SARS-CoV-2 Mpro.

机构信息

School of Life Science, Liaoning University, Shenyang, 110036, China.

School of Computer Science and Software Engineering, University of Science and Technology Liaoning, Anshan, 114051, China.

出版信息

Comput Biol Med. 2022 Aug;147:105728. doi: 10.1016/j.compbiomed.2022.105728. Epub 2022 Jun 15.

DOI:10.1016/j.compbiomed.2022.105728
PMID:35763931
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9197785/
Abstract

The impact of the ravages of COVID-19 on people's lives is obvious, and the development of novel potential inhibitors against SARS-CoV-2 main protease (Mpro), which has been validated as a potential target for drug design, is urgently needed. This study developed a model named MproI-GEN, which can be used for the de novo design of potential Mpro inhibitors (MproIs) based on deep learning. The model was mainly composed of long-short term memory modules, and the last layer was re-trained with transfer learning. The validity (0.9248), novelty (0.9668), and uniqueness (0.0652) of the designed potential MproI library (PMproIL) were evaluated, and the results showed that MproI-GEN could be used to design structurally novel and reasonable molecules. Additionally, PMproIL was filtered based on machine learning models and molecular docking. After filtering, the potential MproIs were verified with molecular dynamics simulations to evaluate the binding stability levels of these MproIs and SARS-CoV-2 Mpro, thereby illustrating the inhibitory effects of the potential MproIs against Mpro. Two potential MproIs were proposed in this study. This study provides not only new possibilities for the development of COVID-19 drugs but also a complete pipeline for the discovery of novel lead compounds.

摘要

新型冠状病毒肺炎（COVID-19）对人们生活的影响是显而易见的，急需开发针对严重急性呼吸综合征冠状病毒 2 主蛋白酶（Mpro）的新型潜在抑制剂。本研究开发了一种名为 MproI-GEN 的模型，可用于基于深度学习从头设计潜在的 Mpro 抑制剂（MproIs）。该模型主要由长短时记忆模块组成，最后一层采用迁移学习重新训练。评估了设计的潜在 MproI 库（PMproIL）的有效性（0.9248）、新颖性（0.9668）和独特性（0.0652），结果表明 MproI-GEN 可用于设计结构新颖且合理的分子。此外，还基于机器学习模型和分子对接对 PMproIL 进行了过滤。过滤后，使用分子动力学模拟对潜在的 MproIs 进行验证，以评估这些 MproIs 与 SARS-CoV-2 Mpro 的结合稳定性水平，从而说明潜在的 MproIs 对 Mpro 的抑制作用。本研究提出了两种潜在的 MproIs。本研究不仅为 COVID-19 药物的开发提供了新的可能性，还为新型先导化合物的发现提供了完整的研究途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/96703d58e64d/mmcfigs4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/6c6df54f0345/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/6b228142f62a/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/ab6e69fea73d/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/a2a9777add18/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/136905c01d14/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/09f61eb5402e/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/f514ab6bda23/gr7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/3840b5d2d65f/gr8_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/d4aa07a3c7a7/mmcfigs1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/32c4b95ffdac/mmcfigs2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/55e556d636dc/mmcfigs3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/96703d58e64d/mmcfigs4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/6c6df54f0345/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/6b228142f62a/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/ab6e69fea73d/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/a2a9777add18/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/136905c01d14/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/09f61eb5402e/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/f514ab6bda23/gr7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/3840b5d2d65f/gr8_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/d4aa07a3c7a7/mmcfigs1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/32c4b95ffdac/mmcfigs2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/55e556d636dc/mmcfigs3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0101/9197785/96703d58e64d/mmcfigs4_lrg.jpg

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