Elucidating the mechanisms of a herbal compound fumarine and its modulation on the estrogen receptor 1

Stroke-related numbness and weakness (SRNW) are resultant disabilities following a stroke episode and may present with muscle weakness, numbness, tightness, spasticity, and pain in up to 85% of patients. Huangqi Guizhi Wuwu Decoction (HGWD) has been widely investigated to manage the sensorimotor deficiencies at the herb and formula level. However, detailed molecular mechanisms of its constituents are presently lacking. This project employed computational molecular modelling and docking methods to identify candidate compounds of HGWD which may serve as effective modulators of target proteins involved in SRNW. Estrogen Receptor 1 was identified as a promising target for HGWD compounds, while the herbal compound fumarine, a constituent of <i>Jujubae Fructus</i>, was predicted to exhibit high binding affinity and favourable ligand-receptor interactions with ESR1. There is currently a lack of scientific evidence for specific atomic-level interactions between ESR1 and this compound. Therefore, molecular docking and molecular dynamics simulations were used to elucidate the interaction mechanisms of fumarine with ESR1; and the molecular-level structural and functional consequences of ligand binding. Ligand-receptor contact analysis and free energy decomposition calculations identified Glu419 and Leu38 as stable hydrogen bond partners, while favourable contributions to the binding free energy include in Met421 (-10.74 kJ/mol) and Leu525 (-10.02 kJ/mol). This work provides the basis for further studies on discovering lead compounds which modulate the activity of ESR1.