ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1560571
Discovery of non-covalent rhinovirus 3Cpro inhibitors by molecular docking, in vitro assays, molecular dynamics simulations and DFT analyses
Provisionally accepted
- 1Shenyang Pharmaceutical University, Shenyang, Liaoning Province, China
- 2Beijing Institute of Pharmacology & Toxicology, Beijing, China
- 3Fifth Medical Center of the PLA General Hospital, Beijing, Beijing Municipality, China
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Human rhinovirus 14 (HRV-14) is a leading cause of the common cold, with its 3C protease (3Cpro) playing a crucial role in viral replication by cleaving polyproteins into functional proteins and enzymes. This makes 3Cpro a promising target for therapeutic intervention. In this study, to identify novel HRV-14 3Cpro noncovalent inhibitors, we performed a virtual screening of the TopScience and TargetMol (USA) database and selected 44 potential compounds for HRV-14 3Cpro inhibitory activity evaluation. Preliminary assays at 50 μM showed that compounds S21, S33, S34, and S43 exhibited inhibition rates of 80.51%, 96.5%, 75.59%, and 88.79%, respectively.Further characterization revealed that S21 and S34 exhibited moderate activity with IC50 values of 30.40 ± 0.67 μM and 24.11 ± 0.55 μM, respectively, while S33 and S43 displayed stronger inhibition with IC50 values of 11.32 ± 0.71 μM and 2.33 ± 0.5 μM, respectively. To elucidate the binding mode of S33 and S43 to HRV-14 3Cpro, we conducted all-atom molecular dynamics (MD) simulations and density functional theory (DFT) calculations on the docked complexes of compounds S33 and S43 with HRV-14 3Cpro. MD analyses, including principal component analysis (PCA), free energy landscapes (FEL), and dynamic cross-correlation matrices (DCCM), revealed that both compounds enhanced the structural stability of the HRV-14 3Cpro while reducing its flexibility and internal dynamics. These findings suggested that S33 and S43 are promising candidates for optimization and clinical development as novel noncovalent HRV-14 3Cpro inhibitors.
Keywords: human rhinovirus, 3Cpro, molecular docking, molecular dynamics, DFT
Received: 16 Jan 2025; Accepted: 25 Apr 2025.
Copyright: © 2025 Zhang, Zong, Ruan, Liu, Zhao, Li, Zhang and Hu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Xingzhou Li, Beijing Institute of Pharmacology & Toxicology, Beijing, China
Youzhi Zhang, Beijing Institute of Pharmacology & Toxicology, Beijing, China
Chun Hu, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, China
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