The ongoing global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the urgent need for effective therapeutic interventions. With millions infected and hundreds of thousands deceased, traditional drug development timelines are insufficient to meet this crisis. In response, structure-based drug repurposing has emerged as a rapid and efficient strategy to identify existing FDA-approved drugs that can be redirected against key viral targets. This study focuses on two critical structural proteins of SARS-CoV-2: the non-structural protein 9 (Nsp9) replicase and the spike glycoprotein—both essential for viral replication and host cell entry.
Using computational methods, we performed virtual screening of 2000 FDA-approved compounds, including antivirals, anti-malarials, anti-parasitics, anti-fungals, anti-tuberculosis agents, and bioactive phytochemicals. Molecular docking simulations were conducted using PyRx with AutoDock Vina as the engine, targeting the crystal structures of Nsp9 replicase (PDB ID: 6W4B) and the spike protein (PDB ID: 6LZG). The binding affinities were evaluated based on docking scores, with the most negative values indicating stronger interactions. Among the top hits, Conivaptan exhibited the highest binding energy of -8.4 kcal/mol with Nsp9 replicase, forming stable interactions with key residues such as CYS74, LEU107, LEU113, ALA108, ASN34, VAL8, and SER6 at the active site. Tegobuvir showed the strongest affinity (-8.1 kcal/mol) with the spike protein, engaging in crucial contacts with PRO337, ALA344, ARG355, ARG466, and GLU340.
Further analysis confirmed the stability of these ligand-protein complexes through 100 nanosecond molecular dynamics simulations using the Schrödinger suite. The results demonstrated consistent hydrogen bonding, hydrophobic interactions, and water bridge formation throughout the simulation, particularly for Conivaptan–Nsp9 and Tegobuvir–spike complexes. Ramachandran plots indicated high structural integrity, with over 95% of residues in favored regions. Root mean square deviation (RMSD) and fluctuation (RMSF) analyses confirmed minimal conformational changes, supporting the robustness of the binding mode.
ADME profiling using Swiss-ADME revealed favorable pharmacokinetic properties for both lead compounds. Conivaptan and Tegobuvir adhered to Lipinski’s Rule of Five, demonstrating good oral bioavailability, metabolic stability, and low toxicity risks.163239-22-3 SMILES These features enhance their potential for clinical translation.RGS13 Antibody supplier
In conclusion, our findings identify Conivaptan and Tegobuvir as promising candidates for repurposing in the treatment of COVID-19.PMID:34161955 Their strong binding affinities, stable interactions, and favorable ADME profiles support further investigation in preclinical and clinical settings. Future studies should evaluate their antiviral efficacy in vitro and in vivo, particularly regarding inhibition of viral replication via Nsp9 and suppression of viral entry through spike protein interference. This work exemplifies how computational approaches can accelerate drug discovery during public health emergencies.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com