Ligand-Based Pharmacophore Modeling and Structure-Based Virtual Screening for Identifying Potential Therapeutic...

Area of Science:

• Computational chemistry
• Drug discovery
• Virology

Background:

• Coronavirus disease (COVID-19) presents significant global health challenges due to high mortality and morbidity.
• The SARS-CoV-2 spike protein is a primary target for antiviral drug development.

Purpose of the Study:

• To identify novel inhibitors of the SARS-CoV-2 spike protein using a combination of ligand-based pharmacophore modeling (LBPM) and structure-based virtual screening (SBVS).
• To evaluate the efficacy and safety of identified compounds through in vitro assays.

Main Methods:

• Screening of ligands from the MolPort database using docking and molecular dynamics simulations targeting the SARS-CoV-2 receptor-binding domain (RBD).
• In vitro assays to confirm inhibition of spike-ACE2 binding and assess cytotoxicity.

Main Results:

• Four compounds exhibited favorable docking scores and dynamic stability.
• Compounds C3 and C4 demonstrated significant inhibition of spike-ACE2 binding with IC50 values of 0.03 µM and 10.4 µM, respectively.
• Both compounds showed low cytotoxicity with CC50 values greater than 100 µM.

Conclusions:

• The combined LBPM and SBVS approach is effective for identifying potential antiviral agents.
• 1H-pyrazol-5-ol derivatives show promise as building blocks for developing new antiviral therapies against SARS-CoV-2.