Piperine and novel *Pterocarpus santalinoides* constituent show superior oxytocin receptor binding in silico
Background
Postpartum hemorrhage remains a leading cause of maternal mortality, often managed by administering oxytocin to promote uterine contraction and involution. However, current oxytocin administration can have limitations, prompting the search for alternative or complementary oxytocin receptor (OTR) modulators. Pterocarpus santalinoides, a plant traditionally used in West African medicine for postpartum uterine involution, presents a promising natural source for novel compounds that could enhance or mimic oxytocin's effects, addressing a critical gap in maternal health interventions.
Study Design
This purely in silico study investigated potential OTR modulators from P. santalinoides ethanol leaf extract. Phytochemicals were identified via gas chromatography-mass spectrometry (GC-MS). Oxytocin (PubChem CID: 439302) served as the endogenous reference. The OTR structure (PDB ID: 6TPK) was retrieved. All analyses used Schrödinger Maestro v21.8 suite. QikProp predicted ADMET properties, while Maestro Protein Preparation Wizard and LigPrep prepared protein and ligands. Molecular docking was performed using Glide Extra-Precision (XP) mode. Prime MM-GBSA calculated relative binding-free energy. Complex stability was assessed via 100 ns molecular dynamics (MD) simulations in Desmond using the OPLS4 force field. Of 59 identified phytochemicals, 14 met ADMET criteria for docking.
Results
Several phytochemicals demonstrated stronger predicted binding affinities to the OTR than endogenous oxytocin (-5.680 kcal/mol). Piperine exhibited the highest Glide XP docking score at -7.270 kcal/mol. MM-GBSA analysis further identified E-(5-(benzo[d][1,3]dioxol-5-yl)-1-(piperidin-1-yl)pent-2-en-1-one) as the top-ranked compound with a ΔG_bind of -49.87 kcal/mol. Piperine was confirmed as the overall lead candidate with a ΔG_bind of -46.57 kcal/mol.
Both lead compounds significantly surpassed oxytocin's predicted binding affinity (
ΔG_bind= -40.73 kcal/mol). Crucially, the piperine-OTR complex maintained stability throughout the 100 ns MD simulation, suggesting a robust interaction. These findings highlight specific natural compounds with potent theoretical OTR modulating capabilities.
Key Findings
- Piperine showed the highest
Glide XPdocking score of -7.270 kcal/mol to the OTR. - E-(5-(benzo[d][1,3]dioxol-5-yl)-1-(piperidin-1-yl)pent-2-en-1-one) was the top
MM-GBSAranked compound (ΔG_bind= -49.87 kcal/mol). - Piperine was identified as the overall lead candidate with a
ΔG_bindof -46.57 kcal/mol. - Both lead compounds exhibited stronger predicted binding affinities than endogenous oxytocin (
ΔG_bind= -40.73 kcal/mol). - The piperine-OTR complex demonstrated stability over a 100 ns molecular dynamics simulation.
Why It Matters
Identifying natural compounds like piperine as potent OTR modulators opens new avenues for managing postpartum hemorrhage and enhancing uterine involution. This research provides a strong computational foundation for developing novel therapeutic agents, potentially offering alternatives or adjuncts to synthetic oxytocin. While purely in silico, these findings warrant immediate in vitro and in vivo validation to confirm biological activity and safety. If validated, these compounds could lead to new protocols for maternal health, potentially leveraging traditional plant medicine in a scientifically rigorous manner. The discovery phase is complete; the next step is experimental confirmation.
pterocarpus-santalinoides
piperine
oxytocin-receptor
postpartum-hemorrhage
uterine-involution
in-silico