Theoretical investigation of the anti-proliferative properties of 1, 3-diphenyl-1H-pyrazoles against breast cancer cells; QSAR modeling, DFT, molecular docking, molecular dynamic simulations, and ADMET predictions

Abstract Background Breast cancer is the major cause of cancer-related deaths globally. This public health emergency is further worsened by challenges of drug resistance and toxicities of the current medications. Hence, the search for novel drugs has become very necessary. Methods In this study, some cytotoxic 1, 3-diphenyl-1H-pyrazole derivatives were virtually screened against estrogen receptor alpha (ERα) of breast cancer to identify promising ligands from the dataset of molecules. Afterward, the bioactive ligands were subjected to QSAR modeling and the validated model was used to design more potent analogs of the most active member of the dataset selected as lead/template molecule (Tm). Subsequently, the binding affinity of the designed ligands against the active sites of ERα was investigated with the aid of molecular docking and molecular mechanics generalized born surface area (MM/GBSA) calculations. Furthermore, density functional theory (DFT) calculation and molecular dynamics simulations were used to study the electronic properties and thermodynamic stability of the most promising ligands and their complexes with the receptor, respectively. Finally, the pharmacokinetic and toxicity profiles of the ligands were also investigated. Results The validated penta-parametric QSAR model ( R 2 train = 0.896; R 2 adj = 0.875; Q 2 CV = 0.816; and R 2 test = 0.703) used for designing new bioactive ligands hinted the predominant influence of molecular size, shape, and symmetry on the observed cytotoxic effects of the investigated 1, 3-diphenyl-1H-pyrazole derivatives on breast cancer cells (MCF-7). The designed ligands; DP-1, DP-2, DP-3, DP-4, and DP-5 which bind to the ERα target with Gibbs free energy change (∆ G Total ) of − 41.57, − 42.06, − 42.16, − 41.64, and − 41.91 kcal/mol, respectively, appear more potent than Tm with ∆ G Total value of − 34.89 kcal/mol and tamoxifen (∆ G Total = − 34.89 kcal/mol), an approved drug used herein as positive control. Moreover, the excellent cytotoxic potentials of the new drug candidates against MCF-7 cells were supported by both quantum mechanical calculations and molecular dynamic simulations. In addition, the ligands display sound pharmacokinetic profiles. Conclusion The designed ligands could be excellent sources of novel drug candidates against estrogen receptor positive breast cancer. Hence, further in vitro and in vivo investigations on the bioactive molecules are recommended.