Exploration of 2D and 3D-QSAR analysis and docking studies for novel dihydropteridone derivatives as promising therapeutic agents targeting glioblastoma
Background: Dihydropteridone derivatives represent a novel class of PLK1 inhibitors, exhibiting promising anticancer activity and potential as chemotherapeutic drugs for glioblastoma.Objective: The aim of this study is to develop 2D and 3D-QSAR models to validate the anticancer activity of dihydropt...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1249041/full |
| _version_ | 1797730338627125248 |
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| author | Meichen Pan Lingxue Cheng Yiguo Wang Chunyi Lyu Chao Hou Qiming Zhang |
| author_facet | Meichen Pan Lingxue Cheng Yiguo Wang Chunyi Lyu Chao Hou Qiming Zhang |
| author_sort | Meichen Pan |
| collection | DOAJ |
| description | Background: Dihydropteridone derivatives represent a novel class of PLK1 inhibitors, exhibiting promising anticancer activity and potential as chemotherapeutic drugs for glioblastoma.Objective: The aim of this study is to develop 2D and 3D-QSAR models to validate the anticancer activity of dihydropteridone derivatives and identify optimal structural characteristics for the design of new therapeutic agents.Methods: The Heuristic method (HM) was employed to construct a 2D-linear QSAR model, while the gene expression programming (GEP) algorithm was utilized to develop a 2D-nonlinear QSAR model. Additionally, the CoMSIA approach was introduced to investigate the impact of drug structure on activity. A total of 200 novel anti-glioma dihydropteridone compounds were designed, and their activity levels were predicted using chemical descriptors and molecular field maps. The compounds with the highest activity were subjected to molecular docking to confirm their binding affinity.Results: Within the analytical purview, the coefficient of determination (R2) for the HM linear model is elucidated at 0.6682, accompanied by an R2cv of 0.5669 and a residual sum of squares (S2) of 0.0199. The GEP nonlinear model delineates coefficients of determination for the training and validation sets at 0.79 and 0.76, respectively. Empirical modeling outcomes underscore the preeminence of the 3D-QSAR model, succeeded by the GEP nonlinear model, whilst the HM linear model manifested suboptimal efficacy. The 3D paradigm evinced an exemplary fit, characterized by formidable Q2 (0.628) and R2 (0.928) values, complemented by an impressive F-value (12.194) and a minimized standard error of estimate (SEE) at 0.160. The most significant molecular descriptor in the 2D model, which included six descriptors, was identified as “Min exchange energy for a C-N bond” (MECN). By combining the MECN descriptor with the hydrophobic field, suggestions for the creation of novel medications were generated. This led to the identification of compound 21E.153, a novel dihydropteridone derivative, which exhibited outstanding antitumor properties and docking capabilities.Conclusion: The development of 2D and 3D-QSAR models, along with the innovative integration of contour maps and molecular descriptors, offer novel concepts and techniques for the design of glioblastoma chemotherapeutic agents. |
| first_indexed | 2024-03-12T11:42:51Z |
| format | Article |
| id | doaj.art-b3c0365993ef49e38d49c8fd9feff505 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-12T11:42:51Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-b3c0365993ef49e38d49c8fd9feff5052023-08-31T12:48:59ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-08-011410.3389/fphar.2023.12490411249041Exploration of 2D and 3D-QSAR analysis and docking studies for novel dihydropteridone derivatives as promising therapeutic agents targeting glioblastomaMeichen Pan0Lingxue Cheng1Yiguo Wang2Chunyi Lyu3Chao Hou4Qiming Zhang5First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, ChinaDepartment of Gastroenterology, 960th Hospital of the Chinese People’s Liberation Army, Jinan, ChinaMedical Laboratory Center, Chinese Academy of Traditional Chinese Medicine, Beijing, ChinaFirst Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, ChinaDepartment of Gastroenterology, 960th Hospital of the Chinese People’s Liberation Army, Jinan, ChinaMedical Laboratory Center, Chinese Academy of Traditional Chinese Medicine, Beijing, ChinaBackground: Dihydropteridone derivatives represent a novel class of PLK1 inhibitors, exhibiting promising anticancer activity and potential as chemotherapeutic drugs for glioblastoma.Objective: The aim of this study is to develop 2D and 3D-QSAR models to validate the anticancer activity of dihydropteridone derivatives and identify optimal structural characteristics for the design of new therapeutic agents.Methods: The Heuristic method (HM) was employed to construct a 2D-linear QSAR model, while the gene expression programming (GEP) algorithm was utilized to develop a 2D-nonlinear QSAR model. Additionally, the CoMSIA approach was introduced to investigate the impact of drug structure on activity. A total of 200 novel anti-glioma dihydropteridone compounds were designed, and their activity levels were predicted using chemical descriptors and molecular field maps. The compounds with the highest activity were subjected to molecular docking to confirm their binding affinity.Results: Within the analytical purview, the coefficient of determination (R2) for the HM linear model is elucidated at 0.6682, accompanied by an R2cv of 0.5669 and a residual sum of squares (S2) of 0.0199. The GEP nonlinear model delineates coefficients of determination for the training and validation sets at 0.79 and 0.76, respectively. Empirical modeling outcomes underscore the preeminence of the 3D-QSAR model, succeeded by the GEP nonlinear model, whilst the HM linear model manifested suboptimal efficacy. The 3D paradigm evinced an exemplary fit, characterized by formidable Q2 (0.628) and R2 (0.928) values, complemented by an impressive F-value (12.194) and a minimized standard error of estimate (SEE) at 0.160. The most significant molecular descriptor in the 2D model, which included six descriptors, was identified as “Min exchange energy for a C-N bond” (MECN). By combining the MECN descriptor with the hydrophobic field, suggestions for the creation of novel medications were generated. This led to the identification of compound 21E.153, a novel dihydropteridone derivative, which exhibited outstanding antitumor properties and docking capabilities.Conclusion: The development of 2D and 3D-QSAR models, along with the innovative integration of contour maps and molecular descriptors, offer novel concepts and techniques for the design of glioblastoma chemotherapeutic agents.https://www.frontiersin.org/articles/10.3389/fphar.2023.1249041/fullglioblastomadrug designdihydropteridone derivativesQSARmolecule docking |
| spellingShingle | Meichen Pan Lingxue Cheng Yiguo Wang Chunyi Lyu Chao Hou Qiming Zhang Exploration of 2D and 3D-QSAR analysis and docking studies for novel dihydropteridone derivatives as promising therapeutic agents targeting glioblastoma Frontiers in Pharmacology glioblastoma drug design dihydropteridone derivatives QSAR molecule docking |
| title | Exploration of 2D and 3D-QSAR analysis and docking studies for novel dihydropteridone derivatives as promising therapeutic agents targeting glioblastoma |
| title_full | Exploration of 2D and 3D-QSAR analysis and docking studies for novel dihydropteridone derivatives as promising therapeutic agents targeting glioblastoma |
| title_fullStr | Exploration of 2D and 3D-QSAR analysis and docking studies for novel dihydropteridone derivatives as promising therapeutic agents targeting glioblastoma |
| title_full_unstemmed | Exploration of 2D and 3D-QSAR analysis and docking studies for novel dihydropteridone derivatives as promising therapeutic agents targeting glioblastoma |
| title_short | Exploration of 2D and 3D-QSAR analysis and docking studies for novel dihydropteridone derivatives as promising therapeutic agents targeting glioblastoma |
| title_sort | exploration of 2d and 3d qsar analysis and docking studies for novel dihydropteridone derivatives as promising therapeutic agents targeting glioblastoma |
| topic | glioblastoma drug design dihydropteridone derivatives QSAR molecule docking |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1249041/full |
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