3CLpro of SARS-CoV-2 as a new target for bufadienolides: in silico and in vitro study
文献类型：期刊论文
| 作者 | Kayumov, Muzaffar11; Razzokov, Jamoliddin8,9,10; Makhkamov, Mukhriddin7; Radjabov, Murodjon6; Mukhamedov, Nurkhodja6,11; Khakimov, Makhmudjon11; Asrorov, Akmal M.5,11; Khasanov, Okhunjon4; Yashinov, Ansor3,11; Tashmukhamedov, Mugrajitdin2,11 |
| 刊名 | JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
 |
| 出版日期 | 2025-07-05 |
| 卷号 | 39期号:1页码:15 |
| 关键词 | Bufadienolides 3CL(pro) Computer simulations Molecular dynamics Umbrella sampling In vitro analysis |
| ISSN号 | 0920-654X |
| DOI | 10.1007/s10822-025-00623-2 |
| 通讯作者 | Kayumov, Muzaffar(mqayumov0808@gmail.com) |
| 英文摘要 | The rapid spread of SARS-CoV-2 and its widespread public health implications have highlighted the urgent need for effective antiviral therapies. A promising strategy is to investigate natural compounds that may inhibit the key viral targets. In this work, we demonstrated the anti-SARS-CoV-2 activity of six bufadienolides, including bufalin (A), arenobufagin (B), gamabufotalin (C), telocinobufagin (D), marinobufagin (E), and bufarenogin (F) from the venom of the Central Asian green toad, Bufo viridis. Molecular docking assays revealed that all A-F bufadienolides bind to key residues (Thr26, His41, Met49, Met161, and Gln189) in the catalytic pocket of 3-chymotrypsin-like cysteine protease (3CL(pro)), an essential enzyme for viral replication and polyprotein processing. The stability of the protein-ligand complexes was then tested using molecular dynamics (MD) simulations, while the binding free energies were estimated using the umbrella sampling (US) technique. Compounds A (-49.8 +/- 1.0 kJ/mol), C (-45.9 +/- 1.8 kJ/mol), E (-45.6 +/- 1.1 kJ/mol), and F (-45.8 +/- 1.9 kJ/mol) had significantly higher binding affinities than compounds B (-14.6 +/- 1.1 kJ/mol) and D (-10.3 +/- 1.9 kJ/mol). In vitro enzymatic assays also confirmed these results, demonstrating that A and C exhibited potent inhibitory activity against 3CL(pro) with IC50 values of 1.37 mu M and 2 mu M, respectively, compared to the other bufadienolides; however, they were less active than the positive control GC376 (IC50 = 0.27 mu M). The experimental results are consistent with the computational observations. In silico ADME profiling also revealed good pharmacokinetic properties, indicating that bufadienolides A-F are lead compounds for further antiviral drug development. Taken together, our results support the hypothesis that bufadienolides are SARS-CoV-2 3CL(pro) inhibitors and elucidate their mechanism of action, thereby laying the foundation for potential therapeutic advances against COVID-19. |
| WOS关键词 | FORCE-FIELD ; DYNAMICS ; SOLUBILITY |
| 资助项目 | Ministry of Innovative Development of the Republic of Uzbekistan[F-FA-2021-359] ; Ministry of Higher Education, Science and Innovation of the Republic of Uzbekistan[2024VBA0019] ; PIFI Fund of the Chinese Academy of Sciences |
| WOS研究方向 | Biochemistry & Molecular Biology ; Biophysics ; Computer Science |
| 语种 | 英语 |
| WOS记录号 | WOS:001528410500003 |
| 出版者 | SPRINGER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318813]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Kayumov, Muzaffar |
| 作者单位 | 1.Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Beijing Rd 40-1, Urumqi 830011, Peoples R China 2.Tashkent Inst Chem Technol, Navoi Str 32, Tashkent 100011, Uzbekistan 3.Chinese Acad Sci, Shanghai Inst Mat Med, Haike Rd 501, Shanghai 201203, Peoples R China 4.Kimyo Int Univ, Dept Med Biol Sci, Shota Rustaveli 156, Tashkent 100121, Uzbekistan 5.Alfraganus Univ, Yukori Karakamish Str 2a, Tashkent 100190, Uzbekistan 6.Natl Univ Uzbekistan, Dept Nat Cpds & Appl Chem, Univ 4, Tashkent 100174, Uzbekistan 7.Tashkent Int Univ Educ, Imom Bukhoriy 6, Tashkent 100207, Uzbekistan 8.Tashkent State Tech Univ, Dept Biotechnol, Univ 2, Tashkent 100095, Uzbekistan 9.Shakhrisabz State Pedag Inst, Dept Nat Sci, Shakhrisabz St 10, Kashkadarya 181301, Uzbekistan 10.Natl Res Univ TIIAME, Inst Fundamental & Appl Res, Kori Niyoziy 39, Tashkent 100000, Uzbekistan |
| 推荐引用方式 GB/T 7714 | Kayumov, Muzaffar,Razzokov, Jamoliddin,Makhkamov, Mukhriddin,et al. 3CLpro of SARS-CoV-2 as a new target for bufadienolides: in silico and in vitro study[J]. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,2025,39(1):15. |
| APA | Kayumov, Muzaffar.,Razzokov, Jamoliddin.,Makhkamov, Mukhriddin.,Radjabov, Murodjon.,Mukhamedov, Nurkhodja.,...&Mirzaakhmedov, Sharafitdin.(2025).3CLpro of SARS-CoV-2 as a new target for bufadienolides: in silico and in vitro study.JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,39(1),15. |
| MLA | Kayumov, Muzaffar,et al."3CLpro of SARS-CoV-2 as a new target for bufadienolides: in silico and in vitro study".JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 39.1(2025):15. |
入库方式： OAI收割
来源：上海药物研究所
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