Rational approaches to discover SARS-CoV-2/ACE2 interaction inhibitors: Pharmacophore-based virtual screening, molecular docking, molecular dynamics and binding free energy studies

The lack of effective treatment remains a bottleneck in combating the current coronavirus family pandemic, particularly coronavirus 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection of host cells by SARS-CoV-2 is mediated by the binding of its receptor-binding domain (RBD) on the spike (S) glycoprotein to the host angiotensin-converting enzyme (ACE2) receptor. As all developed and available vaccines against COVID-19 do not provide long-term immunity, the creation of an effective drug for the treatment of COVID-19 is necessary and cannot be ignored. Therefore, the aim of this study is to present a computational screening method to identify potential inhibitor candidates with a high probability of blocking the binding of RBD to the ACE2 receptor. Pharmacophore mapping, molecular docking, molecular dynamics (MD) simulations, and binding free-energy analyses were performed to identify potential inhibitor candidates against ACE2/SARS-CoV-2. In conclusion, we propose the compound PubChem-84280085 as a potential inhibitor of protein–protein interactions to disrupt the binding of the SARS-CoV-2-RBD to the ACE2 receptor.