Diversifying the chloroquinoline scaffold against SARS-COV-2 main protease: Virtual screening approach using cross-docking, sitemap analysis and molecular dynamics simulation

Abstract

The absence of designated coronavirus disease 19 (Covid-19) remedies and lack of treatment protocols drove scientists to propose new small molecules and to attempt to repurpose existing drugs against various targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in order to bring forward efficient solutions. The main protease (Mpro) is one of the most promising drug targets due to its crucial role in fighting viral replication. Several antiviral drugs have been used in an attempt to overcome the pandemic, such as Hydroxychloroquine (HCQ). Despite its perceived positive outcomes in the beginning of the disease, HCQ was associated with a few drawbacks such as insolubility, toxicity, and cardiac adverse effects. Therefore, in the present study, we have performed a structure-based virtual screening approach to identify structurally modified ligands of chloroquinoline (CQ) scaffold with good solubility, absorption, and permeation aiming to eventually suggest a more dependable alternative. PDB ID: 7BRP Mpro was chosen as the most reliable receptor after cross-docking calculation using 30 crystal structures. Then, a SiteMap analysis was carried out and a total of 231,456 structurally modified compounds of CQ scaffold were suggested. After Lipinski criteria filtration, 64,312 molecules were docked and their MM-GBSA free binding energy was calculated. Next, ADME descriptors were calculated, and 12 molecules with ADME properties better than that of HCQ were identified. The resultant molecules were subjected to molecular dynamics (MD) simulation for 100 ns. The results of the study indicate that 3 molecules (CQ_22; CQ_2 and CQ_56) show better interactions and stability with the Mpro receptor. Binding interaction analysis indicates that GLU143, THR26, and HIS41 amino acids are potential binding hot-spot residues for the remaining 3 ligands.