Enhancing cancer drug development with xanthone derivatives: A QSAR approach and comparative molecular docking investigations

Xanthone compounds are known to have diverse pharmacological activities, including anti-inflammatory, anticancer properties. However, they face challenges such as poor water solubility and a tendency to convert into phase 2 conjugates. Therefore, new strategies are needed to develop improved derivatives. Thus, this study aims to establish a mathematical 2D-QSAR model to predict the pGI50 values of potential xanthone derivatives against breast cancer. For this study, the anti-breast cancer activity (pGI50) values of 27 xanthone derivatives tested against MCF-7 cell lines were retrieved from the National Cancer Institute (NCI) data library. Regression analysis was performed using various physiochemical and Density Functional Theory (DFT)-based descriptors to model a 2D-QSAR equation. The model was internally and externally validated, and the most reactive xanthone derivatives were identified. Based on the QSAR equation, 10 new molecules were computationally designed, and their pGI50 values were determined. The applicability domain (AD) was defined, and the Y-randomization test confirmed the validity and reliability of the QSAR model. DFT calculations were carried out for these molecules, of which Mol 1, Mol 2, Mol 8, and Mol 10 exhibited high reactivity. However, it was found that only Mol 8 fell within the AD, making it suitable for further investigation through molecular docking studies involving cancer proteins. During the molecular docking analyses, the binding energy and interactions between Mol 8 and the target proteins were evaluated. The results showed that Mol 8 exhibited superior binding energy and interactions compared to the native ligands. Additionally, Mol 8 demonstrated more favorable ADMET properties than the native ligands. These findings suggest that Mol 8 holds promise for designing novel and more potent compounds due to its advantageous characteristics and interactions with the target proteins.(c) 2023 SAAB. Published by Elsevier B.V. All rights reserved.

Automated summary

This study established a 2D-QSAR model to predict the activity of potential xanthone derivatives against breast cancer. New molecules were computationally designed and evaluated for their activity and interactions through molecular docking analysis. Among them, Mol 8 exhibited superior binding energy and ADMET properties, making it a promising candidate for designing novel compounds.