Corticosteroid Prednisolone and flavonoid Chrysin as drug candidates against SARS-CoV-2 replication: Computational...

The rapid evolution of SARS-CoV-2 and the emergence of new variants have resulted in mutations in the Spike protein's receptor-binding domain (RBD), enhancing its binding affinity to the ACE2 receptor and increasing viral transmissibility. This study aims to identify inhibitors that can disrupt the Spike-ACE2 interaction, potentially preventing viral entry and immune evasion. The selected compounds may emerge as putative drugs following further studies.

FDA-approved compounds were screened using molecular docking and molecular dynamics (MD) simulations to identify potential inhibitors of the Spike-ACE2 interaction. The most promising candidates were further validated through in vitro assays, including sandwich ELISA and Microscale Thermophoresis, to assess their ability to reduce Spike-ACE2 complex formation. The shortlisted compounds were tested in a cell-based viral culture system to evaluate their impact on SARS-CoV-2 replication.

Ten compounds were initially identified as potential inhibitors. Further in vitro validation narrowed the selection to five compounds that significantly reduced the formation of the Spike-ACE2 complex. Among them, Chrysin (a flavonoid) and Prednisolone (a corticosteroid) demonstrated the highest efficacy in suppressing the interaction, with IC₅₀ values of 1.93 μM and 13.27 μM, respectively. Compounds could inhibit virus replication in the culture.

Chrysin and Prednisolone emerged as the most effective inhibitors of the Spike-ACE2 interaction. Their potential to suppress SARS-CoV-2 replication suggests they could be valuable therapeutic candidates. Further studies, including animal model evaluations, are needed to explore their clinical applicability.