Machine Learning-Based Virtual Screening and Molecular Simulation Approaches Identified Novel Potential Inhibitors for Cancer Therapy

Cyclin-dependent kinase 2 (CDK2) is a promising target for cancer treatment, developing new effective CDK2 inhibitors is of great significance in anticancer therapy. The involvement of CDK2 in tumorigenesis has been debated, but recent evidence suggests that specifically inhibiting CDK2 could be ben...

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Main Authors: Muhammad Shahab, Guojun Zheng, Abbas Khan, Dongqing Wei, Alexander S. Novikov
Format: Article
Language:English
Published: MDPI AG 2023-08-01
Series:Biomedicines
Subjects:
Online Access:https://www.mdpi.com/2227-9059/11/8/2251
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author Muhammad Shahab
Guojun Zheng
Abbas Khan
Dongqing Wei
Alexander S. Novikov
author_facet Muhammad Shahab
Guojun Zheng
Abbas Khan
Dongqing Wei
Alexander S. Novikov
author_sort Muhammad Shahab
collection DOAJ
description Cyclin-dependent kinase 2 (CDK2) is a promising target for cancer treatment, developing new effective CDK2 inhibitors is of great significance in anticancer therapy. The involvement of CDK2 in tumorigenesis has been debated, but recent evidence suggests that specifically inhibiting CDK2 could be beneficial in treating certain tumors. This approach remains attractive in the development of anticancer drugs. Several small-molecule inhibitors targeting CDK2 have reached clinical trials, but a selective inhibitor for CDK2 is yet to be discovered. In this study, we conducted machine learning-based drug designing to search for a drug candidate for CDK2. Machine learning models, including k-NN, SVM, RF, and GNB, were created to detect active and inactive inhibitors for a CDK2 drug target. The models were assessed using 10-fold cross-validation to ensure their accuracy and reliability. These methods are highly suitable for classifying compounds as either active or inactive through the virtual screening of extensive compound libraries. Subsequently, machine learning techniques were employed to analyze the test dataset obtained from the zinc database. A total of 25 compounds with 98% accuracy were predicted as active against CDK2. These compounds were docked into CDK2’s active site. Finally, three compounds were selected based on good docking score, and, along with a reference compound, underwent MD simulation. The Gaussian naïve Bayes model yielded superior results compared to other models. The top three hits exhibited enhanced stability and compactness compared to the reference compound. In conclusion, our study provides valuable insights for identifying and refining lead compounds as CDK2 inhibitors.
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spelling doaj.art-fe652efe2e5c46b597b8f756b04148272023-11-19T00:21:31ZengMDPI AGBiomedicines2227-90592023-08-01118225110.3390/biomedicines11082251Machine Learning-Based Virtual Screening and Molecular Simulation Approaches Identified Novel Potential Inhibitors for Cancer TherapyMuhammad Shahab0Guojun Zheng1Abbas Khan2Dongqing Wei3Alexander S. Novikov4State Key Laboratories of Chemical Resources Engineering, Beijing University of Chemical Technology, Beijing 100029, ChinaState Key Laboratories of Chemical Resources Engineering, Beijing University of Chemical Technology, Beijing 100029, ChinaDepartment of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, ChinaDepartment of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, ChinaInstitute of Chemistry, Saint Petersburg State University, Saint Petersburg 199034, RussiaCyclin-dependent kinase 2 (CDK2) is a promising target for cancer treatment, developing new effective CDK2 inhibitors is of great significance in anticancer therapy. The involvement of CDK2 in tumorigenesis has been debated, but recent evidence suggests that specifically inhibiting CDK2 could be beneficial in treating certain tumors. This approach remains attractive in the development of anticancer drugs. Several small-molecule inhibitors targeting CDK2 have reached clinical trials, but a selective inhibitor for CDK2 is yet to be discovered. In this study, we conducted machine learning-based drug designing to search for a drug candidate for CDK2. Machine learning models, including k-NN, SVM, RF, and GNB, were created to detect active and inactive inhibitors for a CDK2 drug target. The models were assessed using 10-fold cross-validation to ensure their accuracy and reliability. These methods are highly suitable for classifying compounds as either active or inactive through the virtual screening of extensive compound libraries. Subsequently, machine learning techniques were employed to analyze the test dataset obtained from the zinc database. A total of 25 compounds with 98% accuracy were predicted as active against CDK2. These compounds were docked into CDK2’s active site. Finally, three compounds were selected based on good docking score, and, along with a reference compound, underwent MD simulation. The Gaussian naïve Bayes model yielded superior results compared to other models. The top three hits exhibited enhanced stability and compactness compared to the reference compound. In conclusion, our study provides valuable insights for identifying and refining lead compounds as CDK2 inhibitors.https://www.mdpi.com/2227-9059/11/8/2251CDK2machine learningvirtual screeningmolecular dockingMD simulation
spellingShingle Muhammad Shahab
Guojun Zheng
Abbas Khan
Dongqing Wei
Alexander S. Novikov
Machine Learning-Based Virtual Screening and Molecular Simulation Approaches Identified Novel Potential Inhibitors for Cancer Therapy
Biomedicines
CDK2
machine learning
virtual screening
molecular docking
MD simulation
title Machine Learning-Based Virtual Screening and Molecular Simulation Approaches Identified Novel Potential Inhibitors for Cancer Therapy
title_full Machine Learning-Based Virtual Screening and Molecular Simulation Approaches Identified Novel Potential Inhibitors for Cancer Therapy
title_fullStr Machine Learning-Based Virtual Screening and Molecular Simulation Approaches Identified Novel Potential Inhibitors for Cancer Therapy
title_full_unstemmed Machine Learning-Based Virtual Screening and Molecular Simulation Approaches Identified Novel Potential Inhibitors for Cancer Therapy
title_short Machine Learning-Based Virtual Screening and Molecular Simulation Approaches Identified Novel Potential Inhibitors for Cancer Therapy
title_sort machine learning based virtual screening and molecular simulation approaches identified novel potential inhibitors for cancer therapy
topic CDK2
machine learning
virtual screening
molecular docking
MD simulation
url https://www.mdpi.com/2227-9059/11/8/2251
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