The COVID-19 pandemic, caused by SARS-CoV-2, has emerged as a global health crisis, leading to widespread morbidity and mortality, causing significant disruption to daily life and socio-economic activities worldwide. The outbreak created an urgent need for novel therapeutics and vaccines. However, several of these pharmaceutical interventions have exhibited adverse effects with prolonged usage, emphasizing the need for alternative or complementary therapeutic approaches. Withania somnifera (known as Ashwagandha) has gained attention due to its long history of use in traditional medicine and its reported antiviral, immunomodulatory, and anti-inflammatory properties. This study investigates the binding affinities and molecular interactions of particularly three bioactive compounds in detail – Ashwagandhanolide, Sitoindoside IX and Withanolide D – using molecular docking techniques. The analysis revealed binding affinities of -9.5 kcal/mol, -8.8 kcal/mol and -8.9 kcal/mol, respectively. Detailed interaction profiles identified ADMET profiling pharmacophore modeling, van der Waals forces, hydrogen bonding, and hydrophobic interactions as key contributors to drug-likeness and stability of these compounds. These findings provide insights into the compounds’ potential pharmacological applications and establish a foundation for experimental validation in the future. • The utility of AlphaFold-generated high-confidence structural models of SARS-CoV-2 ORF9b protein to accurately identify ligand-binding sites, enabling precise molecular docking of Ashwagandha-derived compounds. • Withanolide D and Sitoindoside IX can be promising ORF9b inhibitors, based on their strong binding affinities, substantial dipole moments, and favourable hydrogen bonding interactions, indicating their potential for antiviral drug development. • Computational analysis including binding affinity, dipole moment assessments, hydrogen bond network evaluations, ADMET profiling and pharmacophore modeling, to evaluate drug-likeness and antiviral efficacy.
Patel et al. (Sun,) studied this question.