Sanachai, Kamonpan and Somboon, Tuanjai and Wilasluck, Patcharin and Deetanya, Peerapon and Wolschann, Peter and Langer, Thierry and Lee, Vannajan Sanghiran and Wangkanont, Kittikhun and Rungrotmongkol, Thanyada and Hannongbua, Supot (2022) Identification of repurposing therapeutics toward SARS-CoV-2 main protease by virtual screening. PLoS ONE, 17 (6). ISSN 1932-6203, DOI https://doi.org/10.1371/journal.pone.0269563.
Full text not available from this repository.Abstract
SARS-CoV-2 causes the current global pandemic coronavirus disease 2019. Widely-available effective drugs could be a critical factor in halting the pandemic. The main protease (3CL(pro)) plays a vital role in viral replication; therefore, it is of great interest to find inhibitors for this enzyme. We applied the combination of virtual screening based on molecular docking derived from the crystal structure of the peptidomimetic inhibitors (N3, 13b, and 11a), and experimental verification revealed FDA-approved drugs that could inhibit the 3CL(pro) of SARS-CoV-2. Three drugs were selected using the binding energy criteria and subsequently performed the 3CL(pro) inhibition by enzyme-based assay. In addition, six common drugs were also chosen to study the 3CL(pro) inhibition. Among these compounds, lapatinib showed high efficiency of 3CL(pro) inhibition (IC50 value of 35 +/- 1 mu M and K-i of 23 +/- 1 mu M). The binding behavior of lapatinib against 3CL(pro) was elucidated by molecular dynamics simulations. This drug could well bind with 3CL(pro) residues in the five subsites S1', S1, S2, S3, and S4. Moreover, lapatinib's key chemical pharmacophore features toward SAR-CoV-2 3CL(pro) shared important HBD and HBA with potent peptidomimetic inhibitors. The rational design of lapatinib was subsequently carried out using the obtained results. Our discovery provides an effective repurposed drug and its newly designed analogs to inhibit SARS-CoV-2 3CL(pro).
| Item Type: | Article |
|---|---|
| Funders: | Thailand Science Research and Innovation Fund Chulalongkorn University (CU) [CU_FRB65_hea (71)_134_23_64], Thailand Science Research and Innovation Fund Chulalongkorn University (CU) [08/2559], Second Century Fund (C2F),Chulalongkorn University, (Institute for the Promotion of Teaching Science and Technology IPST) under the Research Fund for DPST Graduate with First Placement [08/2559], 90th Anniversary of the CU Scholarship, Science Achievement Scholarship of Thailand (SAST), National Council of Thailand (NRCT) [N42A650231] |
| Uncontrolled Keywords: | Molecular-dynamics; Drug discovery; 3cl proteases; Docking; Coronavirus; Inhibitor; Pharmacophores; Site |
| Subjects: | R Medicine > RS Pharmacy and materia medica |
| Divisions: | Faculty of Science > Department of Chemistry |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 15 Jul 2024 08:26 |
| Last Modified: | 16 Jul 2024 07:17 |
| URI: | http://eprints.um.edu.my/id/eprint/40442 |
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