In Silico Multi-Target Approach Revealed Potential Lead Compounds as Scaffold for the Synthesis of Chemical Analogues Targeting SARS-CoV-2

Simple Summary COVID-19 is an infectious disease caused by SARS-CoV-2. The virus has rapidly spread to humans, causing the ongoing coronavirus pandemic. Enormous progress in finding therapies has been made, but an effective therapy is still absent. In this study, we propose a computational strategy aimed at identifying novel multi-target scaffolds against the virus. The proposed study was performed using bioinformatics methods, such as homology modeling, virtual screening and classical molecular dynamics, where 3D structures of targets were reconstructed and compounds with potential inhibitory activity against different virus targets were identified. Furthermore, a potential mechanism of action was proposed. Our study could provide new insights and approaches for the rapid identification of novel multi-target inhibitors of SARS-CoV-2. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infectious disease that spreads rapidly in humans. In March 2020, the World Health Organization (WHO) declared a COVID-19 pandemic. Identifying a multi-target-directed ligand approach would open up new opportunities for drug discovery to combat COVID-19. The aim of this work was to perform a virtual screening of an exclusive chemical library of about 1700 molecules containing both pharmacologically active compounds and synthetic intermediates to propose potential protein inhibitors for use against SARS-CoV-2. In silico analysis showed that our compounds triggered an interaction network with key residues of the SARS-CoV-2 spike protein (S-protein), blocking trimer formation and interaction with the human receptor hACE2, as well as with the main 3C-like protease (3CLpro), inhibiting their biological function. Our data may represent a step forward in the search for potential new chemotherapeutic agents for the treatment of COVID-19.