Evaluation of selected indigenous spices- and herbs-derived small molecules as potential inhibitors of SREBP and its implications for breast cancer using MD simulations and MMPBSA calculations.

In this study, we conducted an extensive analysis of 252 bioactive compounds derived from native spices and herbs for their potential anti-breast cancer activity against sterol regulatory element-binding protein (SREBP), using in silico techniques. To evaluate the oral bioavailability, overall pharmacokinetics, and safety profiles of these compounds, we employed Lipinski's rule of five and ADME descriptors, which depicted 66 lead molecules. These molecules were then docked with the SREBP using molecular docking tools, which revealed that diosgenin and smilagenin were the most promising hits compared to the reference inhibitor betulin, with average binding affinities of - 7.42 and - 7.37 kcal/mol and - 6.27 kcal/mol, respectively. To further assess the stability of these complexes along with betulin, we conducted molecular dynamics simulations over a 100 ns simulation period. We employed various parameters, including the root-mean-square deviation, root-mean-square fluctuation, solvent-accessible surface area, free energy of solvation, and radius of gyration, followed by principal component analysis. Furthermore, we evaluated the toxicity of the selected compounds against various anticancer cell lines, as well as their metabolic activity related to CYP450 metabolism and biological activity spectrum. Based on these results, both molecules exhibited promising drug candidate potential and could be utilized for further experimental analysis to elucidate their anticancer potential.