Cenk Serhan OZVEREL, Emine ERDAG, Ahmet Ozer SEHIRLI
Journal of Research in Pharmacy - 2026;30(4):1157-1169
Since the development of immune checkpoint drugs targeting PD-1 and PD-L1, cancer immunotherapy has advanced significantly. However, there are drawbacks to using monoclonal antibodies for this purpose, such as their high manufacturing costs and potential immunological side effects. Small molecule inhibitors such as Selective Estrogen Receptor Modulators (SERMs) could offer a potential alternative for cancer immunotherapy targeting PD-L1. This study aimed to evaluate the binding energies and interactions of 17 selected SERMs with the PD-L1 protein using molecular docking, Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) calculations, and umbrella sampling methods, in comparison to benchmark PD-L1 inhibitors. Raloxifene emerged as the top-performing compound, demonstrating superior binding affinities (-85.80 +/- 1.20 kJ/mol, MM/PBSA; -84.90 +/- 1.10 kJ/mol, umbrella sampling) compared to the BMS series of known PD-L1 inhibitors and other SERMs. Interaction analyses highlighted significant stabilizing interactions between raloxifene and key PD-L1 residues. Other SERMs, such as lasofoxifene and ormeloxifene, also demonstrated competitive binding affinities, reinforcing the versatility of SERMs as potential PD-L1 inhibitors. This preliminary study underscored the promise of SERMs as effective and accessible alternatives in cancer immunotherapy. However, further experimental validation is warranted to establish their efficacy in preclinical and clinical settings in the future.
