Substituted 1,4-naphthoquinones for potential anticancer therapeutics: In vitro cytotoxic effects and QSAR-guided design of new analogs
1,4-Naphthoquinone is a promising pharmacophore in drug discovery due to its unique redox reactive nature and wide-ranging bioactivities. Herein, a series of 1,4-naphthoquinones (1-14) were investigated for their anticancer activities against 4 cancer cell lines (i.e., HepG2, HuCCA-1, A549, and MOLT...
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Elsevier
2025-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037025003046 |
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| author | Veda Prachayasittikul Prasit Mandi Ratchanok Pingaew Supaluk Prachayasittikul Somsak Ruchirawat Virapong Prachayasittikul |
| author_facet | Veda Prachayasittikul Prasit Mandi Ratchanok Pingaew Supaluk Prachayasittikul Somsak Ruchirawat Virapong Prachayasittikul |
| author_sort | Veda Prachayasittikul |
| collection | DOAJ |
| description | 1,4-Naphthoquinone is a promising pharmacophore in drug discovery due to its unique redox reactive nature and wide-ranging bioactivities. Herein, a series of 1,4-naphthoquinones (1-14) were investigated for their anticancer activities against 4 cancer cell lines (i.e., HepG2, HuCCA-1, A549, and MOLT-3). Compound 11 was found to be the most potent and selective anticancer agent against all tested cell lines (IC50 = 0.15 – 1.55 μM, selectivity index = 4.14 – 43.57). QSAR modelling was performed to elucidate key structural features influencing activities against four cancer cell lines. Four QSAR models were successfully constructed using multiple linear regression (MLR) algorithm providing good predictive performance (R: training set = 0.8928–0.9664; testing set = 0.7824–0.9157; RMSE: training set = 0.1755–0.2600; testing set = 0.2726–0.3748). QSAR models suggested that the potent anticancer activities of these naphthoquinones were mainly influenced by polarizability (MATS3p and BELp8), van der Waals volume (GATS5v, GATS6v, and Mor16v), mass (G1m), electronegativity (E1e), and dipole moment (Dipole and EEig15d) as well as ring complexity (RCI) and shape of the compound (SHP2). The models were further applied for guiding the design and predicting activities of an additional set of 248 structurally modified compounds in which the ones with promising predicted activities were highlighted for potential further development. Additionally, pharmacokinetic profiles and possible binding modes towards potential biological targets of the compounds were virtually assessed. Structure-activity relationship analysis was also conducted to highlight key structural features beneficial for further successful design of the related naphthoquinones. |
| format | Article |
| id | doaj-art-e5d5306478ab4527934231c0f7e18f19 |
| institution | DOAJ |
| issn | 2001-0370 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Computational and Structural Biotechnology Journal |
| spelling | doaj-art-e5d5306478ab4527934231c0f7e18f192025-08-20T02:57:27ZengElsevierComputational and Structural Biotechnology Journal2001-03702025-01-01273492350910.1016/j.csbj.2025.07.040Substituted 1,4-naphthoquinones for potential anticancer therapeutics: In vitro cytotoxic effects and QSAR-guided design of new analogsVeda Prachayasittikul0Prasit Mandi1Ratchanok Pingaew2Supaluk Prachayasittikul3Somsak Ruchirawat4Virapong Prachayasittikul5Center for Research Innovation and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand; Corresponding authors.Department of Community Medical Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, ThailandDepartment of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand; Corresponding authors.Center for Research Innovation and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, ThailandChulabhorn Research Institute, Bangkok 10210, Thailand; Program in Chemical Sciences, Chulabhorn Graduate Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), CHE, Ministry of Education, ThailandDepartment of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand1,4-Naphthoquinone is a promising pharmacophore in drug discovery due to its unique redox reactive nature and wide-ranging bioactivities. Herein, a series of 1,4-naphthoquinones (1-14) were investigated for their anticancer activities against 4 cancer cell lines (i.e., HepG2, HuCCA-1, A549, and MOLT-3). Compound 11 was found to be the most potent and selective anticancer agent against all tested cell lines (IC50 = 0.15 – 1.55 μM, selectivity index = 4.14 – 43.57). QSAR modelling was performed to elucidate key structural features influencing activities against four cancer cell lines. Four QSAR models were successfully constructed using multiple linear regression (MLR) algorithm providing good predictive performance (R: training set = 0.8928–0.9664; testing set = 0.7824–0.9157; RMSE: training set = 0.1755–0.2600; testing set = 0.2726–0.3748). QSAR models suggested that the potent anticancer activities of these naphthoquinones were mainly influenced by polarizability (MATS3p and BELp8), van der Waals volume (GATS5v, GATS6v, and Mor16v), mass (G1m), electronegativity (E1e), and dipole moment (Dipole and EEig15d) as well as ring complexity (RCI) and shape of the compound (SHP2). The models were further applied for guiding the design and predicting activities of an additional set of 248 structurally modified compounds in which the ones with promising predicted activities were highlighted for potential further development. Additionally, pharmacokinetic profiles and possible binding modes towards potential biological targets of the compounds were virtually assessed. Structure-activity relationship analysis was also conducted to highlight key structural features beneficial for further successful design of the related naphthoquinones.http://www.sciencedirect.com/science/article/pii/S2001037025003046NaphthoquinoneAnticancerQSARADMETComputer-aided drug design |
| spellingShingle | Veda Prachayasittikul Prasit Mandi Ratchanok Pingaew Supaluk Prachayasittikul Somsak Ruchirawat Virapong Prachayasittikul Substituted 1,4-naphthoquinones for potential anticancer therapeutics: In vitro cytotoxic effects and QSAR-guided design of new analogs Computational and Structural Biotechnology Journal Naphthoquinone Anticancer QSAR ADMET Computer-aided drug design |
| title | Substituted 1,4-naphthoquinones for potential anticancer therapeutics: In vitro cytotoxic effects and QSAR-guided design of new analogs |
| title_full | Substituted 1,4-naphthoquinones for potential anticancer therapeutics: In vitro cytotoxic effects and QSAR-guided design of new analogs |
| title_fullStr | Substituted 1,4-naphthoquinones for potential anticancer therapeutics: In vitro cytotoxic effects and QSAR-guided design of new analogs |
| title_full_unstemmed | Substituted 1,4-naphthoquinones for potential anticancer therapeutics: In vitro cytotoxic effects and QSAR-guided design of new analogs |
| title_short | Substituted 1,4-naphthoquinones for potential anticancer therapeutics: In vitro cytotoxic effects and QSAR-guided design of new analogs |
| title_sort | substituted 1 4 naphthoquinones for potential anticancer therapeutics in vitro cytotoxic effects and qsar guided design of new analogs |
| topic | Naphthoquinone Anticancer QSAR ADMET Computer-aided drug design |
| url | http://www.sciencedirect.com/science/article/pii/S2001037025003046 |
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