STRUCTURE BASED COMPUTATIONAL IDENTIFICATION OF POTENTIAL THERAPEUTIC LEADS TARGETING MSH3 PROTEIN

Huntington’s disease is a progressive neurological condition characterized by motor dysfunction, cognitive decline, and psychiatric disturbances. Recent studies indicate that abnormalities in DNA mismatch repair mechanisms, particularly involving the MSH3 protein, contribute to the expansion of CAG repeats and the progression of the disease. In the current investigation, an integrated in-silico strategy was employed to identify small molecules capable of interacting with the MSH3 protein and to evaluate their pharmacological suitability for therapeutic development. Primarily, selected phytochemicals and FDA approved reference drugs used in Huntington’s disease management, including tetrabenazine, deutetrabenazine, and valbenazine, were subjected to drug likeness and toxicity assessment using SwissADME and ProTox. Nine phytochemicals satisfied key ADMET criteria, demonstrating favorable gastrointestinal absorption, blood brain barrier permeability, and low predicted toxicity. Sequence similarity analysis using BLASTp confirmed the high conservation and correct identification of the MSH3 protein sequence, supporting its selection as a reliable computational target. Physicochemical analysis indicated that MSH3 possesses a slightly basic character, moderate conformational flexibility, and an overall hydrophilic nature. Structural validation using PROCHECK revealed that the experimentally determined structure (PDB ID: 3THX) exhibited superior stereochemical stability compared with models generated using trRosetta and AlphaFold. Molecular docking analysis demonstrated that tetrabenazine and deutetrabenazine showed the strongest binding affinity (-7.1 kcal/mol), whereas valbenazine showed -6.7 kcal/mol. Among the test ligands, valeric acid exhibited the most favorable interaction (-4.9 kcal/mol), followed by methyl isobutyl ketone (-4.2 kcal/mol) and isobutyric acid (-4.0 kcal/mol). These findings provide preliminary insights into ligandMSH3 interactions and may guide future structure based therapeutic development for Huntington’s disease.