QSAR and chemical read-across analysis of 370 potential MGMT inactivators to identify the structural features influencing inactivation potency
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Authors
Sun, G.Bai, P.
Fan, T.
Zhao, L.
Zhong, R.
McElhinney, R. S.
McMurry, T. B. H.
Donnelly, D. J.
McCormick, J. E.
Kelly, Jane
Margison, Geoffrey P
Affiliation
Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, ChinaIssue Date
2023
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O6-methylguanine-DNA methyltransferase (MGMT) constitutes an important cellular mechanism for repairing potentially cytotoxic DNA damage induced by guanine O6-alkylating agents and can render cells highly resistant to certain cancer chemotherapeutic drugs. A wide variety of potential MGMT inactivators have been designed and synthesized for the purpose of overcoming MGMT-mediated tumor resistance. We determined the inactivation potency of these compounds against human recombinant MGMT using [3H]-methylated-DNA-based MGMT inactivation assays and calculated the IC50 values. Using the results of 370 compounds, we performed quantitative structure-activity relationship (QSAR) modeling to identify the correlation between the chemical structure and MGMT-inactivating ability. Modeling was based on subdividing the sorted pIC50 values or on chemical structures or was random. A total of nine molecular descriptors were presented in the model equation, in which the mechanistic interpretation indicated that the status of nitrogen atoms, aliphatic primary amino groups, the presence of O-S at topological distance 3, the presence of Al-O-Ar/Ar-O-Ar/R..O..R/R-O-C=X, the ionization potential and hydrogen bond donors are the main factors responsible for inactivation ability. The final model was of high internal robustness, goodness of fit and prediction ability (R2pr = 0.7474, Q2Fn = 0.7375-0.7437, CCCpr = 0.8530). After the best splitting model was decided, we established the full model based on the entire set of compounds using the same descriptor combination. We also used a similarity-based read-across technique to further improve the external predictive ability of the model (R2pr = 0.7528, Q2Fn = 0.7387-0.7449, CCCpr = 0.8560). The prediction quality of 66 true external compounds was checked using the "Prediction Reliability Indicator" tool. In summary, we defined key structural features associated with MGMT inactivation, thus allowing for the design of MGMT inactivators that might improve clinical outcomes in cancer treatment.Citation
Sun G, Bai P, Fan T, Zhao L, Zhong R, McElhinney RS, et al. QSAR and Chemical Read-Across Analysis of 370 Potential MGMT Inactivators to Identify the Structural Features Influencing Inactivation Potency. Pharmaceutics. 2023 Aug 21;15(8). PubMed PMID: 37631385. Pubmed Central PMCID: PMC10458236. Epub 2023/08/26. eng.Journal
PharmaceuticsDOI
10.3390/pharmaceutics15082170PubMed ID
37631385Additional Links
https://doi.org/10.3390/pharmaceutics15082170Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.3390/pharmaceutics15082170