Validation of combination of protodioscin and shatavarin iv from medicinal extracts for alleviating menopausal symptoms by computational deep learning models

• Deep learning models were implemented on large-scale datasets to predict the additivity between Protodioscin and Shatavarin-IV, to evaluate their combined therapeutic outcomes. • The Loewe’s additivity score was predicted using regression analysis to assess the level of additiveness between the molecules, categorizing the interaction as synergistic, additive, or antagonistic. • Through molecular docking simulations, the binding affinity of the phytoestrogens to neuronal receptors was evaluated, providing insights into their potential therapeutic efficacy and mechanisms of action. • The bioavailability, metabolic stability, toxicity, drug interactions, and solubility of both compounds were predicted to assess their potential for clinical use, ensuring safety and efficacy. • Dose-response curves indicated optimal dosages, and the inhibition kinetics of these compounds on proteins associated with menopausal symptoms were studied to determine the most effective doses. Shatavarin-IV and Protodioscin, saponins of Asparagus racemosus and Trigonella foenum-graecum respectively are phytoestrogens commonly used to alleviate post-menopausal symptoms such as hot flashes, sleeping disorder, and mood sways. While their individual benefits are well-documented, the synergistic effects of these compounds remain underexplored. This study aims to validate the combination of Shatavarin-IV and Protodioscin on molecular mediators of menopausal symptoms using advanced computational analyses. Deep learning model for drug additivity analysis was developed and trained on the DrugComb database using the Loewe’s additivity score as the target variable, with a focus on combinations tested on the MCF7 cell line and validated of the 786-O cell line. Molecular docking simulations were performed using PyRx, PyMOL, FPocket and ChimeraX to investigate the binding affinities of Protodioscin and Shatavarin-IV with key neuronal modulators of hot flashes, including Kisspeptin, Neurokinin B, TRPV1, c-FOS, and GnRH. IC50 values were derived from binding free energies. Dose-response simulations were evaluated across concentrations (0.01 µM to 100 µM) using a four-parameter logistic equation. Absorption, Distribution, Metabolism, and Elimination (ADME) profiling was determined to predict bioavailability and toxicity. The dose-response simulations confirmed significant therapeutic potential at relevant concentrations and additive interaction between both the compounds suggests enhanced therapeutic efficacy. ADME profiling indicated favorable bioavailability, non-toxicity, and efficient metabolism for both compounds and provides novel insights into their molecular mechanism of action in the body. The results of this research indicate that the combined additive effect of Protodioscin and Shatavarin-IV in alleviating menopausal symptoms exhibits favorable pharmacokinetic profile, and could potentially be promising candidates for future human clinical studies.