EXPLORING THE NEUROPROTECTIVE POTENTIAL OF GEISSOSPERMINE AND HARMINE ON DOPAMINE D1 RECEPTORS: AN IN SILICO STUDY

Abstract

Objective: This study aims to explore the binding affinities and interaction mechanisms of the phytocompounds geissospermine and harmine with the Dopamine D1 receptor (D1R), providing insight into their potential as therapeutic agents for neurological disorders. Methods: The three-dimensional structure of the Dopamine D1 receptor was obtained from the Protein Data Bank (PDB), while the structures of geissospermine and harmine were retrieved from the PubChem database. Preliminary screenings, including secondary structure validation and pharmacokinetic profiling, were conducted to assess the suitability of these compounds for docking studies. Molecular docking was performed using AutoDock Vina to predict the binding affinities and interaction profiles of geissospermine and harmine with D1R. To further validate these interactions, Molecular Dynamics (MD) simulations were conducted using GROMACS v2019.4 to assess the stability and behavior of the geissospermine-D1R complex over time. Parameters such as Root mean Square Deviation (RMSD) were analyzed to evaluate the dynamic stability of the protein-ligand interactions. Results: Molecular docking revealed that geissospermine exhibited a higher binding affinity towards D1R with a binding energy of-8.6 kcal/mol, interacting with key residues including ILE 1009, ARG 1008, ASN 311, VAL 22, GLU 85, THR 26, ALA 57, LEU 25, and PHE 29. Harmine, while also demonstrating significant interactions, showed a slightly lower binding affinity of-7.2 kcal/mol and formed interactions with residues such as SER 310, LYS 81, ASP 314, ALA 84, TRP 90, CYS 186, TRP 99, and PHE 92. MD simulations confirmed the stable binding of geissospermine to D1R, as reflected by consistent RMSD values over the simulation period. Conclusion: Geissospermine’s superior binding affinity and stable interaction with D1R highlight its potential as a therapeutic candidate for neurological disorders, particularly Huntington’s disease, where modulation of dopamine signaling could yield significant clinical benefits. These findings warrant further investigation into the neuroprotective potential of geissospermine in dopaminergic dysfunction.