2,4,6-Trimethoxy chalcone derivatives: an integrated study for redesigning novel chemical entities as anticancer agents through QSAR, molecular docking, ADMET prediction, and computational simulation

Abstract

QSAR, an efficient and successful approach for optimizing lead compounds in drug design, was employed to study a reported series of compounds derived from 2,4,6-trimethoxy chalcone derivatives. The ability of these compounds to inhibit CDK1 was examined, with the help of QSARINS software for model development. The generated QSAR model revealed three significant descriptors, exhibiting strong correlations with impressive statistical values: cross-validation leave-one-out correlation coefficient (Q²LOO) = 0.6663, coefficient of determination (R²) = 0.7863, external validation coefficient (R²_ext) = 0.7854, cross-validation leave-many-out correlation coefficient (Q²LMO) = 0.6256, Concordance Correlation Coefficient for cross-validation (CCC_cv) = 0.8150, CCC_tr = 0.8804, and CCC_ext = 0.8750. From the key structural findings and the insights gained from the descriptors, ETA_dPsi_A, WTPT-5, and GATS7s, new lead molecules were designed. The designed molecules were then evaluated for their CDK1 inhibitory activity using the three-descriptor model developed in this study. To evaluate their drug likeliness, in-silico ADMET predictions were made using Schrodinger’s Software. Molecular docking was carried out to determine the interactions of designed compounds with the target protein. The designed compounds having excellent binding pocket molecular stability and anticancer effectiveness was substantiated by the findings of the molecular dynamics simulation. The results of this work point out important properties and crucial interactions necessary for efficient protein inhibition, suggesting lead candidates for further development as novel anticancer agents.

Communicated by Ramaswamy H. Sarma

Keywords:

• ADMET
• CDK1
• 2
• 4
• 6-trimethoxy chalcone
• docking
• simulation SASA
• Rg

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Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.