In-silico analysis of Pterocarpus santalinoides constituents as potential oxytocin receptor modulators

Pterocarpus santalinoides, a plant widely used in West African traditional medicine for postpartum uterine involution, has prompted investigation into its potential molecular mechanisms involving the oxytocin receptor (OTR). This study evaluated interactions of phytochemical compounds identified via gas chromatography-mass spectrometry (GC-MS) in the ethanol leaf extract of P. santalinoides with the OTR (PDB ID: 6TPK), using oxytocin (PubChem CID: 439302) as the endogenous pharmacological reference ligand. Compounds were sourced from PubChem, and the OTR structure was retrieved from the RCSB PDB. All analyses and simulations were performed within the Schrödinger Maestro v21.8 suite (Schrödinger LLC). Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were predicted using the QikProp tool (Maestro v21.8, Schrödinger LLC), while protein and ligand preparation was performed using the Maestro Protein Preparation Wizard and LigPrep tools. Molecular docking was conducted using Glide Extra-Precision (XP) mode, followed by Prime MM-GBSA calculations for relative binding-free energy ranking. Complex stability was assessed through 100 ns molecular dynamics (MD) simulations in Desmond employing the OPLS4 force field. Of 59 GC-MS-identified phytochemicals, 14 compounds satisfied the ADMET criteria and were advanced to docking. Several phytochemicals exhibited stronger predicted binding affinities than the endogenous reference oxytocin (- 5.680 kcal/mol), with piperine showing the highest docking score (- 7.270 kcal/mol). MM-GBSA analysis identified E-(5-(benzo[d][1,3]dioxol-5-yl)-1-(piperidin-1-yl)pent-2-en-1-one) as the top-ranked compound (ΔG_bind = - 49.87 kcal/mol) and piperine as the overall lead candidate (ΔG_bind = - 46.57 kcal/mol) by both surpassing oxytocin (ΔG_bind = - 40.73 kcal/mol). Piperine-OTR complex stability was confirmed across the 100 ns MD simulation. In conclusion, this purely in silico study identifies candidate OTR-interacting phytochemicals from P. santalinoides, with piperine emerging as a promising lead, and generates testable hypotheses for future experimental validation.

The online version contains supplementary material available at 10.1007/s40203-026-00686-5.