Molecular Docking, ADME, toxicity, and flexibility analysis of compounds in Withania somnifera L. for dopamine D2 receptor inhibition

Withania somnifera L., often referred to as Ashwagandha or Indian ginseng, is a therapeutic herb originating from the Indian subcontinent, where it has been utilized in conventional medicine and Ayurvedic for more than 3,000 years. The dopamine D2 receptor (D2R) is essential for nervous system function, and abnormalities in its activity is linked to conditions like Parkinson's disease, schizophrenia, and substance addiction. However, many drugs targeting D2R can cause severe, sometimes life-threatening side effects because of their non-selective binding to related receptors. The purpose of this study is to examine the inhibitory effects of withaferin A, withanolide A, B, C, D, E, F, withanone, and sitoindoside IX found in W. somnifera on the D2R using molecular docking techniques. The crystal structure of the D2R (PDB: 6CM4) and the structures of the chemical compounds were procured from the RCSB Protein Data Bank and PubChem database, respectively. The preparation of the target protein and ligands was carried out using UCSF Chimera 1.17.3. Docking simulations were conducted between the D2R and risperidone, an atypical antipsychotic drug used as the reference inhibitor, along with nine compounds from W. somnifera. The Autodock Vina plugin within UCSF Chimera 1.17.3 was used for the docking process with default settings. The results were analyzed using BIOVIA Discovery Studio. Flexibility analysis of protein-ligand complexes obtained from molecular docking was performed using CABS-Flex 2.0.The ProTox 3.0 web server was used to predict the potential toxicological profiles of the compounds. As a result, the binding energies of all compounds were found to be below -5 kcal/mol. SwissADME analysis confirmed that all of these compounds adhere to Lipinski's Rule of 5 except sitoindoside IX. The findings from this research are anticipated to provide important guidance for future drug development targeting dopamine D2 receptors.