Molecular Dynamics and Simulation Studies on Herbal Contraceptives as Progesterone Receptor modulators

The necessity for contraceptive solutions with improved safety profiles has driven the exploration of plant derived compounds as alternatives to synthetic hormonal agents like levonorgestrel. We report an extensive in-silico investigation of phytochemicals that may serve as progesterone receptor (PR) modulators for contraception. By employing ADMET profiling, structure-activity relationship predictions, and molecular docking, 64 phytochemicals were evaluated as possible progesterone receptor modulators based on their antifertility, anti-implantation, and antiovulatory properties. Diosgenin from the bark of Crateva nurvala was found to have the highest binding affinity ($-10.8 \mathrm{kcal} / \mathrm{mol}$), outperforming levonorgestrel ($-10.4 \mathrm{kcal} / \mathrm{mol})$. Molecular dynamics simulations over 10 ns revealed that levonorgestrel had slightly superior binding stability, with a lower average potential energy ($1.11025 e^{+}+06 \mathrm{~kJ} / \mathrm{mol}$ vs. $\mathbf{- 1. 1 0 9 9 8 e + 0 6} \mathbf{k J} / \mathrm{mol}$ for diosgenin) and more consistent hydrogen bonding. The root mean square deviation (RMSD) analysis revealed that levonorgestrel had generally lower RMSD values with occasional sharp peaks, whereas diosgenin had a greater RMSD and gradually increased to 1.5 nm. The root mean square fluctuation analysis revealed that levonorgestrel increased the protein’s flexibility whereas diosgenin promoted a more rigid structure. Additionally, luteolin from the bark or leaf of Vitex negundo showed promise, with a binding affinity of $-9.1 \mathrm{kcal} / \mathrm{mol}$. Our findings suggest that diosgenin and luteolin merit further investigation as probable plant-derived contraceptives, with in vivo studies required to validate their efficacy and safety profiles.