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 (IC 50 = 0.03 µM) and C4 (IC 50 = 10.4 µM) effectively inhibited spike–ACE2 binding with low cytotoxicity (CC 50 > 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.