VIRTUAL IDENTIFICATION AND SCREENING OF NOVEL VMAT2 INHIBITORS AS THERAPEUTIC CANDIDATES FOR HUNTINGTON’S DISEASE

Abstract

The pathology underlying Huntington’s disease (HD) results from an unusual polyglutamine tract attributed to a mutation on the short arm of chromosome number 4, in the huntingtin gene, leading to hyperkinetic movement and psychiatric dysfunctions. Presently, HD treatment is palliative in nature and major symptom i.e., chorea is managed by use of Anti-Dopaminergic Medications (ADMs) comprising of Vesicular Monoamine Transporters (VMATs) inhibitors and antipsychotic medications. A subset of VMAT inhibitors specifically Vesicular Monoamine Transporter Type 2 (VMAT2) assist in lowering amount of vesicular monoamines, for instance, dopamine and block its release from pre-synaptic vesicles. As a result, dopamine fails to reach upregulated D2 receptors and therefore reduces chorea. In this study, Valbenazine (VBZ), an FDA approved VMAT2 inhibitor in 2023 for HD mediated chorea is chosen as reference pertaining to its higher efficacy, longer serum shelf-life, safety and reduced psychiatric manifestations as compared to other VMAT2 inhibitors namely Tetrabenazine (TBZ) and Deutetrabenazine (DBZ). The structures similar in conformation to Valbenazine are selected for molecular docking and identifying potential alternatives to VBZ. The potential ligands were also assessed by ADME analysis. The compound CID 163809280 exhibited the strongest interaction with VMAT2, yielding a binding energy of -10.8 kcal/mol suggesting highest favourable binding among the tested ligands.

Result: Initial screening of chemical structures retrieved from PubChem yielded about 1,156 structures, which were further filtered on the basis of structural similarity to the lead drug candidate Valbenazine (VBZ). Out of the shortlisted nine compounds, docking analysis revealed that compound CID 163809280 exhibited highest binding energy of -10.8 kcal/mol.

Conclusion: ADMET analysis of compound CID 163809280 (binding energy of -10.8 kcal/mol) highlighted its drug-likeness capability and BBB permeability rendering its potential use as a VMAT2 inhibitor. In subsequent studies, experimental determination of binding affinity is recommended to validate these in silico results.