Molecular Dynamic Simulation And 3d-Pharmacophore Modeling Of Alpha Mangostin And Its Derivatives Against Estrogen Alpha Receptor

Abstract

Background: Human estrogen receptor alpha (ERα), which is known to play a role in mediating cell proliferation, metastasis, and resistance to apoptosis, is one of the targets of breast cancer therapies. Alpha mangostin (AM) is an active xanthone compound from Garcinia mangostana L. which has activity as an ERα inhibitor. Objectives: This research aims to predict the pharmacokinetic and toxicity and to study the molecular interactions of AM derivatives with the ERα using computer-aided simulation approaches through molecular docking, molecular dynamic, and pharmacophore screening to develop novel anti-breast cancer agents. Methods: Marvinsketch and Chimera programs were used to design and optimize the structure of AM and its derivatives. For screening the pharmacokinetic and toxicity profiles, the PreADMET web was used. The AutoDockTools 1.5.6 and LigandScout 4.4.3 Advanced software were used to conduct the molecular docking simulation and pharmacophore screening, respectively, while the molecular dynamic simulation was performed using AMBER 16. The results were visualized by Biovia Discovery Studio. method: Marvinsketch and Chimera program were used to design and optimize the stucture of AM and its derivatives. For screening the pharmacokinetic and toxicity profiles, the PreADMET web was used. The AutoDockTools 1.5.6 and LigandScout 4.4.3 Advanced software was used to conduct the molecular docking simulation and pharmacophore screening, respectively, while the molecular dynamic simulation was performed using AMBER 16. The results were visualized by Biovia Discovery Studio. Results: Molecular docking using Autodock showed that FAT10 derivate has lower binding free energy (G) (-12.04 kcal/mol) than AM (-8.45 kcal/mol) when docking to ERα and both performed the same hydrogen bond with Thr347. These support the results of the MMPBSA calculation on dynamic simulation which shows FAT10 (-58.4767 kcal/mol) has lower G than AM (-42.7041 kcal/mol) and 4-OHT (-49.0821 kcal/mol). The pharmacophore screening results also showed that FAT10 fitted the pharmacophore with a fit score of 47.08. result: Molecular docking of ERα using Autodock showed that FAT10 derivate has lower free energy binding (G) (-12.04 kcal/mol) than alpha mangostin (-8.45 kcal/mol) and both formed hydrogen bond with Thr347. The results are supported by the MMPBSA calculation on dynamic simulation with FAT10 (-58.4767 kcal/mol) having lower G than alpha mangostin (-42.7041 kcal/mol) and 4-OHT (-49.0821 kcal/mol). The pharmacophore screening also showed that FAT10 fit score is 47.08, indicating that it fitted the pharmacophore model. Conclusion: From the results, it can be suggested that FAT10 has promising activity as ERα antagonist. Further in vitro and in vivo experiments should be carried out to support these in silico studies,