Lomitapide as a Potential Estrogen Receptor Inhibitor: A Computational Drug Repurposing Study

Authors : Zekeriya Düzgün, Funda Demırtaş Korkmaz

Pages : 8-14

Doi:10.30934/kusbed.1347829

View : 85 | Download : 96

Publication Date : 2024-03-15

Article Type : Research

Abstract :Objective: Estrogen receptor (ER) inhibitors have significant therapeutic potential for hormone-dependent cancers and related disorders. Tamoxifen, a well-known selective estrogen receptor modulator, has been widely used as adjuvant therapy for estrogen receptor-positive breast cancer. However, tamoxifen may exhibit a tendency to develop resistance with prolonged usage and particularly elevate the risk of uterine cancer. Therefore, there is a need for the discovery and development of new ER modulators or inhibitors. In this study, we identified potential estrogen receptor inhibitors through computational drug repositioning. Methods: A set of 2048 compounds, encompassing FDA-approved drugs and active metabolites, were subjected to molecular docking, molecular dynamics simulations, and free energy calculations to evaluate their interaction with estrogen receptor α (ERα). Results: Among the compounds evaluated, conivaptan, atogepant, and lomitapide exhibited the highest affinities for ERα. Lomitapide displayed a superior docking score (-12 kcal/mol) compared to the established ER inhibitor, tamoxifen (-10 kcal/mol). Further investigation using molecular dynamics simulations and free energy calculations disclosed lomitapide\'s heightened binding affinity of -380.727 kJ/mol, surpassing tamoxifen\'s binding affinity of -352.029 kJ/mol. Conclusion: This comprehensive computational exploration underscores lomitapide\'s potential as a compelling candidate with an envisaged stronger estrogen receptor affinity than the acknowledged standard, tamoxifen. To validate lomitapide\'s promise as a novel ER inhibitor, essential in vitro and in vivo studies are suggested. These investigations will provide essential insights into lomitapide\'s reposition in addressing the challenges tied to hormone-dependent cancers and associated maladies.
Keywords : Estrogen Receptor Antagonists, Drug Repositioning, Lomitapide, Tamoxifen, Molecular Docking, Molecular Dynamics Simulation