Machine Learning-Enabled Exploration of Bryophyllum Pinnatum Phytoconstituents for Urolithiasis Management: Molecular Docking, MMGBSA Analysis, ADMET Profiling, MD simulations, and Toxicity Assessment

Introduction: The development of stones in the urinary tract, particularly in the kidneys, is a common symptom of urolithiasis, commonly referred to as kidney stone disease. The risk of stone formation persists due to lifestyle, metabolic, and genetic factors, and recurrence is high even with advancements in surgical and pharmaceutical treatments. Material and Methods: To treat urolithiasis, this study used an in-silico approach backed by machine learning to examine the therapeutic potential of naturally occurring compounds identified in Bryophyllum pinnatum. Molecular docking, molecular dynamics (MD) simulations, MM-GBSA binding energy analysis, and toxicity profiling were the primary techniques employed. Carbonic anhydrase, urease, calcium-sensing receptor (CaSR), and prostaglandin receptor are vital proteins contributing to kidney stone development. The study aimed to determine the binding and inhibitory potential of the selected phytochemicals against these targets. results: The tested compounds showed considerable binding affinities, with BP1, BP3, BP8, BP10, and BP25 showing potentially significant interactions with the target proteins. Interestingly, compound BP3 had a docking score of -9.2 kcal/mol against carbonic anhydrase, establishing hydrophobic contacts and persistent hydrogen bonds necessary for potent inhibition. Low RMSD and RMSF values, similar to common reference compounds, were found in molecular dynamics simulations lasting 200 nanoseconds, indicating that the ligand-protein complexes stayed stable during the simulation. Results: The tested compounds showed considerable binding affinities, with BP1, BP3, BP8, BP10, and BP25 exhibiting potentially significant interactions with the target proteins. Interestingly, compound BP3 had a docking score of -9.2 kcal/mol against carbonic anhydrase, forming hydrophobic contacts and stable hydrogen bonds necessary for potent inhibition. Molecular dynamics simulations of 200 nanoseconds revealed low RMSD and RMSF values, similar to standard reference compounds, indicating that the ligand-protein complexes remained stable throughout the simulation. Discussion: BP3 and BP8 were placed in toxicity class 5 based on toxicity evaluations using ADMET predictions and ProTox-II, suggesting low toxicity and a favorable safety profile for potential therapeutic use. The computational results indicate that phytoconstituents from Bryophyllum pinnatum are promising candidates for developing safer and more effective plant-based kidney stone treatments. Conclusion: This study opens the door to targeted phytotherapeutic approaches that may improve urolithiasis treatment strategies.