DefinePK

Abstract

Background: Costunolide, a neuroprotective and anti-inflammatory sesquiterpene lactone, may be utilized for tailored dopaminergic therapy. Molecular docking studies show that, in contrast to Tetrandrine, Eudesmol, and Spathulenol, costunolide possesses high binding receptor receptor and beneficial ADMET characteristics. The most effective modulator of dopaminergic transmission is costunolide because of its low pharmacokinetic risk and high efficiency.
Aim: To evaluate the therapeutic potential and receptor selectivity of costunolide as a dopaminergic modulator through in-silico analysis, including ADMET profiling and molecular docking, for potential application in Parkinson’s disease and related neuropsychiatric disorders.
Methods: An in-silico approach was employed to evaluate costunolide, eudesmol, spathulenol, and tetrandine drug-likeness and receptor interaction profile.  ADMET analysis of the drug properties was conducted through SwissADME and the ESOL cheminformatics platform. Molecular docking simulations performed through AutoDock Tools examined receptors dopamine D1 (PDB ID: 7X2D and D2 (PDB ID: 7JVR). Protein and ligand structures were prepared, optimized, and docked, and binding affinities and BIOVIA Discovery Studio facilitated detection of interaction patterns.
Results: The ADMET characteristics of costunolide, eudesmol and spathulenol show excellent absorption, solubility, permeability through blood brain barrier without violating the Lipinski’s Rule. These compounds additionally demonstrated a distinct absence of PAINS alerts. Out of the four compounds, three exhibited CYP inhibition freedom, while spathulenol exhibited inhibition of CYP2C19. Docking simulations of costunolide eudesmol, spathulenol, and tetrandine show -6.1, -5.7, -6.0, and -6.5kcal/mol respectively against D1 receptor and -5.3, -5.5, -6.3, and -7.0kcal/mol respectively against D2 receptor.
Conclusion: Costunolide demonstrates promising therapeutic attributes and moderate selectivity for the dopamine D1 receptor, supported by robust in-silico ADMET and docking analyses. Future investigations including both in vivo efficacy assessments and chemical structure improvements are warranted to unveil therapeutic potency and receptor binding accuracy