Citation: LIN Feng, FU Xin-Mei, WANG Chao, JIANG Si-Yu, WANG Jing-Hui, ZHANG Shu-Wei, YANG Ling, LI Yan. QSAR, Molecular Docking and Molecular Dynamics of 3C-like Protease Inhibitors[J]. Acta Physico-Chimica Sinica, ;2016, 32(11): 2693-2708. doi: 10.3866/PKU.WHXB201608121 shu

QSAR, Molecular Docking and Molecular Dynamics of 3C-like Protease Inhibitors

LIN Feng ^1, ,
FU Xin-Mei ² ,
WANG Chao ¹ ,
JIANG Si-Yu ¹ ,
WANG Jing-Hui ¹ ,
ZHANG Shu-Wei ¹ ,
YANG Ling ³ ,
LI Yan ¹

1.
School of Chemical Engineering, Dalian University of Technology, Dalian 116024, Liaoning Province, P. R. China;
2.
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, Liaoning Province, P. R. China;
3.
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning Province, P. R. China

Received Date: 31 May 2016
Revised Date: 9 August 2016

Fund Project: The project was supported by the National Natural Science Foundation of China (11201049).

3C-like protease is an extremely important protease involved in the multiplicative process of coronaviruses, including the deadlyMiddle East respiratory syndrome coronavirus (MERS-CoV). 3C-like protease has become a hot research topic in the field of coronavirology. For the first time, a set of ligand-and receptorbased three-dimensional quantitative structure-activity relationships (3D-QSAR) models were carried out via comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to explore the structure-activity correlation of 43 peptidomimetic inhibitors of the 3C-like protease of the bat coronavirus HKU4 (HKU4-CoV), which belongs to the same 2c lineage as MERS-CoV and shows high sequence similarity with MERS-CoV. Based on the ligand-based alignment, an optimal CoMSIAmodel (yielded by steric, electrostatic, H-bond donor and H-bond acceptor fields) was obtained with good predictive power of Q²=0.522, R² ncv=0.996 and R² pre=0.904 (Q²:cross-validated correlation coefficient, R² ncv:non-cross-validated correlation coefficient, R² pre:predicted correlation coefficient for the test set of compounds). Molecular docking and molecular dynamics simulations were performed according to this model to further determine the interaction mechanism between ligands and the receptor. The experimental results show:(1) based on the optimal CoMSIAmodel, the 3D contour maps vividly illustrate that the molecular biological activity is influenced by the steric, electrostatic, H-bond donor and H-bond acceptor interactions of molecular groups. (2) Based on the docking analysis, hydrophobicity, crystal water, His166 andGlu169 have important roles in the ligands and receptor binding process. (3) Molecular dynamics (MD) simulations were carried out for further verification of the reliability of the docking model, and provide two new key residues, Ser24 and Gln192, which have two strong hydrogen bonds with the ligands. Some new compounds were obtained based on the modeling that are potential peptidomimetic inhibitors of 3C-like protease. These results help establish the binding mechanism between 3C-like protease and peptidomimetic inhibitors, and provide a valuable reference for future anti-MERS-CoV drug design.
- MERS-CoV,
- 3C-like protease,
- Peptidomimetic inhibitor,
- 3D-QSAR,
- Molecular docking,
- Molecular dynamics
1. [1]
2. [2]
3. [3]
4. [4]
5. [5]
6. [6]
7. [7]
8. [8]
9. [9]
10. [10]
11. [11]
12. [12]
13. [13]
14. [14]
15. [15]
16. [16]
17. [17]
18. [18]
19. [19]
20. [20]
21. [21]
22. [22]
23. [23]
24. [24]
25. [25]
26. [26]
27. [27]
28. [28]
29. [29]
30. [30]
31. [31]
32. [32]
33. [33]
34. [34]
35. [35]
36. [36]
37. [37]
38. [38]
39. [39]
40. [40]
41. [41]
42. [42]
43. [43]
44. [44]
45. [45]
46. [46]
47. [47]
48. [48]
49. [49]
50. [50]
51. [51]
52. [52]
1. [1]
  Shule Liu . Application of SPC/E Water Model in Molecular Dynamics Teaching Experiments. University Chemistry, 2024, 39(4): 338-342. doi: 10.3866/PKU.DXHX202310029
2. [2]
  Zhi Zhou , Yu-E Lian , Yuqing Li , Hui Gao , Wei Yi . New Insights into the Molecular Mechanism Behind Clinical Tragedies of “Cephalosporin with Alcohol”. University Chemistry, 2025, 40(3): 42-51. doi: 10.12461/PKU.DXHX202403104
3. [3]
  Xiaochen Zhang , Fei Yu , Jie Ma . 多角度数理模拟在电容去离子中的前沿应用. Acta Physico-Chimica Sinica, 2024, 40(11): 2311026-. doi: 10.3866/PKU.WHXB202311026
4. [4]
  Shanghua Li , Malin Li , Xiwen Chi , Xin Yin , Zhaodi Luo , Jihong Yu . 基于高离子迁移动力学的取向ZnQ分子筛保护层实现高稳定水系锌金属负极的构筑. Acta Physico-Chimica Sinica, 2025, 41(1): 2309003-. doi: 10.3866/PKU.WHXB202309003
5. [5]
  Xuzhen Wang , Xinkui Wang , Dongxu Tian , Wei Liu . Enhancing the Comprehensive Quality and Innovation Abilities of Graduate Students through a “Student-Centered, Dual Integration and Dual Drive” Teaching Model: A Case Study in the Course of Chemical Reaction Kinetics. University Chemistry, 2024, 39(6): 160-165. doi: 10.3866/PKU.DXHX202401074
6. [6]
  Yue Wu , Jun Li , Bo Zhang , Yan Yang , Haibo Li , Xian-Xi Zhang . Research on Kinetic and Thermodynamic Transformations of Organic-Inorganic Hybrid Materials for Fluorescent Anti-Counterfeiting Application information: Introducing a Comprehensive Chemistry Experiment. University Chemistry, 2024, 39(6): 390-399. doi: 10.3866/PKU.DXHX202403028
7. [7]
  Yan Li , Xinze Wang , Xue Yao , Shouyun Yu . 基于激发态手性铜催化的烯烃E→Z异构的动力学拆分——推荐一个本科生综合化学实验. University Chemistry, 2024, 39(5): 1-10. doi: 10.3866/PKU.DXHX202309053
8. [8]
  Yaling Chen . Basic Theory and Competitive Exam Analysis of Dynamic Isotope Effect. University Chemistry, 2024, 39(8): 403-410. doi: 10.3866/PKU.DXHX202311093
9. [9]
  Jiayu Gu , Siqi Wang , Jun Ling . Kinetics of Living Copolymerization: A Brief Discussion. University Chemistry, 2025, 40(4): 100-107. doi: 10.12461/PKU.DXHX202406012
10. [10]
  Zheqi Wang , Yawen Lin , Shunliu Deng , Huijun Zhang , Jinmei Zhou . Antiviral Strategies: A Brief Review of the Development History of Small Molecule Antiviral Drugs. University Chemistry, 2024, 39(9): 85-93. doi: 10.12461/PKU.DXHX202403108
11. [11]
  Jinfu Ma , Hui Lu , Jiandong Wu , Zhongli Zou . Teaching Design of Electrochemical Principles Course Based on “Cognitive Laws”: Kinetics of Electron Transfer Steps. University Chemistry, 2024, 39(3): 174-177. doi: 10.3866/PKU.DXHX202309052
12. [12]
  Yeyun Zhang , Ling Fan , Yanmei Wang , Zhenfeng Shang . Development and Application of Kinetic Reaction Flasks in Physical Chemistry Experimental Teaching. University Chemistry, 2024, 39(4): 100-106. doi: 10.3866/PKU.DXHX202308044
13. [13]
  Laiying Zhang , Yinghuan Wu , Yazi Yu , Yecheng Xu , Haojie Zhang , Weitai Wu . Innovation and Practice of Polymer Chemistry Experiment Teaching for Non-Polymer Major Students of Chemistry: Taking the Synthesis, Solution Property, Optical Performance and Application of Thermo-Sensitive Polymers as an Example. University Chemistry, 2024, 39(4): 213-220. doi: 10.3866/PKU.DXHX202310126
14. [14]
  Mi Wen , Baoshuo Jia , Yongqi Chai , Tong Wang , Jianbo Liu , Hailong Wu . Improvement of Fluorescence Quantitative Analysis Experiment: Simultaneous Determination of Rhodamine 6G and Rhodamine 123 in Food Using Chemometrics-Assisted Three-Dimensional Fluorescence Method. University Chemistry, 2025, 40(4): 390-398. doi: 10.12461/PKU.DXHX202405147
15. [15]
  Dexin Tan , Limin Liang , Baoyi Lv , Huiwen Guan , Haicheng Chen , Yanli Wang . Exploring Reverse Teaching Practices in Physical Chemistry Experiment Courses: A Case Study on Chemical Reaction Kinetics. University Chemistry, 2024, 39(11): 79-86. doi: 10.12461/PKU.DXHX202403048
16. [16]
  Chunyang Bao , Ruoxuan Miao , Yuhan Ding , Qingfu Ban , Yusheng Qin , Jie Liu , Zhirong Xin . The Comprehensive Experiment Design of Preparation of Depolymerizable Thermosetting Polymers. University Chemistry, 2025, 40(4): 59-65. doi: 10.12461/PKU.DXHX202405087
17. [17]
  Yiying Yang , Dongju Zhang . Elucidating the Concepts of Thermodynamic Control and Kinetic Control in Chemical Reactions through Theoretical Chemistry Calculations: A Computational Chemistry Experiment on the Diels-Alder Reaction. University Chemistry, 2024, 39(3): 327-335. doi: 10.3866/PKU.DXHX202309074
18. [18]
  Zhiwen HUANG , Qi LIU , Jianping LANG . W/Cu/S cluster-based supramolecular macrocycles and their third-order nonlinear optical responses. Chinese Journal of Inorganic Chemistry, 2025, 41(1): 79-87. doi: 10.11862/CJIC.20240184
19. [19]
  Kai Yang , Gehua Bi , Yong Zhang , Delin Jin , Ziwei Xu , Qian Wang , Lingbao Xing . Comprehensive Polymer Chemistry Experiment Design: Preparation and Characterization of Rigid Polyurethane Foam Materials. University Chemistry, 2024, 39(4): 206-212. doi: 10.3866/PKU.DXHX202308045
20. [20]
  You Wu , Chang Cheng , Kezhen Qi , Bei Cheng , Jianjun Zhang , Jiaguo Yu , Liuyang Zhang . ZnO/D-A共轭聚合物S型异质结高效光催化产H₂O₂及其电荷转移动力学研究. Acta Physico-Chimica Sinica, 2024, 40(11): 2406027-. doi: 10.3866/PKU.WHXB202406027

Get Citation

PDF

XML

Metrics

PDF Downloads(28)
Abstract views(1226)
HTML views(397)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142