Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach

The highly contagious and rapidly spreading SARS-coronavirus 2 (SARS-CoV-2), responsible for Coronavirus Disease 2019 (COVID-19), has been declared a pandemic by the World Health Organization (WHO). The novel SARS-CoV-2 enters host cells through the binding of its viral surface spike glycoprotein (S-protein) to the angiotensin-converting enzyme 2 (ACE2) receptor on human cells. This specific molecular interaction between the virus and host cell presents a promising therapeutic target for identifying antiviral drugs against SARS-CoV-2.

Drug repurposing offers a rapid and viable approach to combating the exponential spread of COVID-19. In this study, a high-throughput virtual screening approach was employed to investigate FDA-approved compounds from the LOPAC library against both the receptor-binding domain of the spike protein (S-RBD) and the ACE2 host cell receptor. The initial screening identified several promising molecules for both targets, which were further analyzed in detail through molecular docking, binding energy calculations, binding mode assessments, molecular dynamics, and simulations.

Notably, GR 127935 hydrochloride hydrate, GNF-5, RS504393, TNP, and eptifibatide acetate demonstrated strong binding to the virus-binding motifs of the ACE2 receptor. Additionally, KT203, BMS195614, KT185, RS504393, and GSK1838705A were identified as potential inhibitors targeting the receptor-binding site of the viral S-protein. These molecules may contribute to controlling the rapid spread of SARS-CoV-2 by inhibiting viral entry while also potentially acting as anti-inflammatory agents to alleviate lung inflammation.

Given the urgent need for effective treatments to combat the COVID-19 global crisis, the timely identification of these candidate drugs is of paramount importance. Further in vivo testing is warranted to validate their anti-SARS-CoV-2 efficacy, which could ultimately help save lives.