IN SILICO PHARMACOKINETIC PROFILING AND MOLECULAR DOCKING OF MARGOLONONE AGAINST THE ONCOGENIC IDH1-R132H MUTANT

Mutations in the isocitrate dehydrogenase 1 (IDH1) enzyme, particularly the R132H substitution, are key drivers of several malignancies, owing to the neomorphic production of the oncometabolite D-2-hydroxyglutarate. Targeting the different catalytic pocket of IDH1-R132H remains a critical therapeutic blueprint. This research mainly examines the biophysical viability and binding effectiveness of Margolonone, a novel bioactive compound, as a potential selective inhibitor of the IDH1 mutant. Computational pharmacokinetic profiling was executed using SwissADME to assess lead-likeness and physicochemical stability. To determine binding effectiveness, molecular docking simulations were performed using AutoDock Vina via the Webina framework. The structural model of the IDH1-R132H mutant (PDB ID: 6ADG) was utilised as the receptor. A highly specific (20 X 20 X 20) Å search space was centred around the mutated His132 residue to evaluate allosteric and competitive binding modes. Pharmacokinetic evaluation revealed that Margolonone exhibits excellent biophysical parameters, strictly bound to Lipinski’s Rule of Five with zero violations. The compound demonstrated an ideal molecular weight of 314.4 g/mol and a favourable lipophilicity profile (XLogP3 = 2.9), suggesting high cell membrane permeability and gastrointestinal absorption. Molecular docking simulations corroborated these favourable properties, yielding a strong, spontaneous binding affinity of -6.607 kcal/mol within the IDH1-R132H active site, driven by specific non-covalent interactions within the target pocket, notably strong hydrogen bonding with the ASN96 residue. The combination of optimal lipophilicity, no structural violations, and a highly favourable binding thermodynamic energy indicates that Margolonone acts as a potent, stable ligand for the IDH1-R132H mutant. These in silico findings present Margolonone as a highly executable pharmacokinetic scaffold, warranting immediate in vitro validation for targeted oncological interventions.