Diversifying the chloroquinoline scaffold against SARS-CoV-2 main protease: Virtual screening approach using cross-docking, SiteMap analysis and molecular dynamics simulation Scientific paper

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Mohamed Aissaoui
Billel Belhani
Abdelmoumen Boilebnane
Abdeslem Bouzina
Salah Eddine Djilani


The absence of designated remedies for coronavirus disease 19 (Covid-19) and the 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 several drawbacks, such as insolubility, toxicity, and cardiac adverse effects. There­fore, in the present study, a structure-based virtual scre­en­ing approach was performed to identify structurally modified ligands of the chloroqu­inoline (CQ) scaf­fold with good solubility, absorption, and permeation aimed at eventually suggesting 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 performed and a total of 231,456 structur­ally modified com­pounds of the CQ scaffold were suggested. After Lipinski criteria filtration, 64,312 mole­cules were docked and their MM-GBSA free binding energy were calculated. Next, ADME descriptors were calculated, and 12 molecules with ADME properties better than that of HCQ were identified. The resulting 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_5) 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.


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M. Aissaoui, B. Belhani, A. Boilebnane, A. Bouzina, and S. E. Djilani, “Diversifying the chloroquinoline scaffold against SARS-CoV-2 main protease: Virtual screening approach using cross-docking, SiteMap analysis and molecular dynamics simulation: Scientific paper”, J. Serb. Chem. Soc., vol. 88, no. 5, pp. 505–520, Apr. 2023.
Theoretical Chemistry


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