Novel Inhibitory Role of Fenofibric Acid by Targeting Cryptic Site on the RBD of SARS-CoV-2

The emergence of the recent pandemic causing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an alarming situation worldwide. It also prompted extensive research on drug repurposing to find a potential treatment for SARS-CoV-2 infection. An active metabolite of the hyperlipidemic drug fenofibrate (also called fenofibric acid or FA) was found to destabilize the receptor-binding domain (RBD) of the viral spike protein and therefore inhibit its binding to human angiotensin-converting enzyme 2 (hACE2) receptor. Despite being considered as a potential drug candidate for SARS-CoV-2, FA's inhibitory mechanism remains to be elucidated. We used molecular dynamics (MD) simulations to investigate the binding of FA to the RBD of the SARS-CoV-2 spike protein and revealed a potential cryptic FA binding site. Free energy calculations were performed for different FA-bound RBD complexes. The results suggest that the interaction of FA with the cryptic binding site of RBD alters the conformation of the binding loop of RBD and effectively reduces its binding affinity towards ACE2. Our study provides new insights for the design of SARS-CoV-2 inhibitors targeting cryptic sites on the RBD of SARS-CoV-2.

Automated summary

The emergence of SARS-CoV-2 has caused a global alarm, leading to extensive research on repurposing drugs to treat the infection. Researchers have found that a metabolite of the drug fenofibrate, called fenofibric acid (FA), can destabilize the receptor-binding domain (RBD) of the viral spike protein, inhibiting its binding to the hACE2 receptor. Through molecular dynamics simulations, the study identified a potential cryptic binding site for FA on the RBD and demonstrated that FA alters the conformation of the binding loop, reducing its affinity for ACE2. This research provides new insights for designing SARS-CoV-2 inhibitors targeting cryptic sites on the RBD.