Ligand-Based Pharmacophore Modeling and Structure-Based Virtual Screening for Identifying Potential Therapeutic Agents Targeting the SARS-CoV-2 Spike Protein-ACE2 Receptor Interaction.

Coronavirus disease (COVID-19) remains a global health concern due to its high mortality and morbidity. In this study, we combined ligand-based pharmacophore modeling (LBPM) with structure-based virtual screening (SBVS) to identify novel inhibitors targeting the SARS-CoV-2 spike protein. Ligands from the MolPort database were screened via docking and molecular dynamics simulations at the receptor-binding domain (RBD). Four compounds showed promising docking scores (-8.7 to -6.4 kcal/mol) and dynamic stability (root mean square deviation < 5 Å). In vitro assays confirmed that compounds C3 (IC50 = 0.03 µM) and C4 (IC50 = 10.4 µM) effectively inhibited spike-ACE2 binding with low cytotoxicity (CC50 > 100 µM). These findings show the efficacy of the LBPM technique and highlight 1H-pyrazol-5-ol derivatives as potential building blocks for developing new antiviral agents against SARS-CoV-2.