In silico characterization of Desmodium gangeticum compounds as dual modulators of MAO-B and 5-HT2A in Parkinson’s disease: an integrated approach combining molecular docking, ADMET profiling, MM-GBSA, QSAR modeling, and molecular dynamics simulation

Abstract

Management of Parkinson’s disease (PD) is challenging: dopaminergic treatments alleviate motor symptoms but exacerbate psychosis, while antipsychotics alleviate hallucinations but exacerbate motor symptoms. To tackle this problem, we combined the in silico profiling of Desmodium gangeticum’s phytochemicals with dual monoamine oxidase‑B (MAO‑B) and 5‑hydroxytryptamine type 2A (5‑HT2A) modulating activity. Docking studies suggested Desmodin and 5,7,2′,4′‑Tetrahydroxy‑6‑prenylisoflavanone as potential MAO‑B modulators and N, N‑Dimethyltryptamine and Tryptamine as 5‑HT2A modulators. ADMET profiling revealed promising central nervous system (CNS) drug-likeness, adequate blood-brain barrier penetration and tolerability. Toxicity prediction showed non-toxicity towards hepatotoxicity, mutagenicity and carcinogenicity. Molecular Mechanics Generalised Born Surface Area (MM-GBSA) calculations and Molecular dynamics (MD) studies supported strong interactions and Automated Quantitative Structure-Activity Relationship (AutoQSAR) indicated bioactivity. Thus, these findings indicate that metabolites of D. gangeticum are potentially effective dual-target candidates for addressing both motor and neuropsychiatric symptoms of PD. Desmodin and 5,7,2′,4′-Tetrahydroxy-6-prenylisoflavanone emerged as lead MAO-B binders, while N, N-Dimethyltryptamine and Tryptamine demonstrated strong 5-HT2A binding affinity; however, docking was performed against an active-state 5-HT2A conformation, and structural contacts suggest agonist-type receptor engagement. The functional direction of 5-HT2A binding antagonist (therapeutic) or agonist (potentially hallucinogenic) cannot be resolved computationally and requires experimental functional validation before these compounds can be considered candidates for reducing PD-related psychosis. All findings remain in silico and require experimental research to advance their development as safer multi-targeted drug candidates for clinical trials.