3D-QSAR, molecular docking, ADMET, simulation dynamic, and retrosynthesis studies on new styrylquinolines derivatives against breast cancer

Abstract

Abstract Breast cancer is the most common illness among women, accounting for 25% of all diagnoses, as stated by the American Cancer Society. Current research focuses on 43 compounds of styrylquinoline derivatives as potential inhibitors of tubulin to design a new drug that could potentially be effective against breast cancer cells in humans. The target compounds were subjected to a three-dimensional quantitative structure-activity relationship/comparative molecular similarity indices analysis (CoMSIA) approach, where CoMSIA models were used; the best results obtained are (Q 2 = 0.84, R 2 = 0.97, r ext 2 {r}_{\text{ext}}^{2} = 0.91), H-bond acceptor field was discovered to be important for increasing inhibitory activity by examining the contour maps (54%), and it plays a key role in the prediction of anticancer activity. Based on the contour maps of the CoMSIA models, we obtained information that allows us to propose four new molecules with higher cancer inhibitory than the 43 compounds found in the literature. The molecular docking was applied to determine the likely types of binding between the tubulin protein (PDB ID: 4O2B) and the proposed compounds, and the results show that M1 has a higher total score of 6.53 and two interactions with important conventional hydrogen bond type, followed by compound M2 with a total score of 5.74. Furthermore, the designed molecules showed better pharmacokinetic properties based on absorption, distribution, metabolism, excretion, and toxicity properties. Molecular dynamics simulations at 100 ns were conducted to confirm the binding stability of the selected ligands (M1 and M2) with tubulin protein. The simulation parameters used in the current study are root mean square deviation, root mean square fluctuation, H-bond, Rg, solvent accessible surface area, and binding energy. As a result, the designed compounds (ligands M1 and M2) have shown noteworthy potential as a drug candidate for experimental in vivo and in vitro testing due to their potential inhibition of breast cancer. Finally, the study of retrosynthesis in this work facilitates the synthesis of drug candidates.