In Silico Naringin-Human Estrogen Receptor Interactions

Abstract

Naringin (NGN) is a flavonoid with proestrogenic actions in bone. In silico studies have placed NGN in the estrogen receptor (ESR) ligand niche. We previously expressed doubts about those results because NGN is 1000 times more soluble than estradiol (EST), which represents a thermodynamic barrier.  We reported that binding of NGN to ESR deltaG was minimal for NGN outside the ESR (-8.32 ± 0.34 Kcal/mol+- sigma).  Since the pharmacological effects are well documented, in this work we delve deeper using the same ESR structure in which NGN was reported to occupy the ligand niche, 3ART, and perform competitive docking, NGN vs EST, and molecular dynamics (MD) assays, with widely used free software (OpenChimera, AutoDock, EADock, CharMM forcefields, Gromacs, NAMD).

EST localizes  in the same site it occupies in the reference crystal with deltaG of -11.3 kcal/mol, NGN binds on the outside to helix 12 of the ESR with higher deltaG of -8.45 kcal/mol.  MD simulations with explicit solvent, 310 K (37°C) and NGN concentration over the one than can occur in the cytosol of treated tissues, revealed very few NGN molecules at less than 5 Angstrons, and none in the site of EST.  In another series of tests, with explicit solvent and NGN in the presence of cyclohexane (CHX), it was observed that NGN occupies sites that exclude CHX and that CHX is located 3 Angstrons from the ESR.

Our results strongly support that NGN would not occupy the EST site spontaneously due to its more polar nature (CHX is closer to the receptor).  Simulations with the open form of the receptor produced similar results. We could not find the source of discrepancy with the literature. One explanation could be that the authors performed docking in vacuum, an environment where the extent of London and diple-dipole interactions is different from what can be verified in saline aqueous medium.