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Acta Physico-Chimica Sinca  2016, Vol. 32 Issue (11): 2693-2708    DOI: 10.3866/PKU.WHXB201608121
ARTICLE     
QSAR, Molecular Docking and Molecular Dynamics of 3C-like Protease Inhibitors
Feng LIN1,Xin-Mei FU2,*(),Chao WANG1,Si-Yu JIANG1,Jing-Hui WANG1,Shu-Wei ZHANG1,Ling YANG3,Yan LI1,*()
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
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Abstract  

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.



Key wordsMERS-CoV      3C-like protease      Peptidomimetic inhibitor      3D-QSAR      Molecular docking      Molecular dynamics     
Received: 31 May 2016      Published: 12 August 2016
MSC2000:  O641  
Fund:  the National Natural Science Foundation of China(11201049)
Corresponding Authors: Xin-Mei FU,Yan LI     E-mail: fuxinmei@dlut.edu.cn;yanli@dlut.edu.cn
Cite this article:

Feng LIN,Xin-Mei FU,Chao WANG,Si-Yu JIANG,Jing-Hui WANG,Shu-Wei ZHANG,Ling YANG,Yan LI. QSAR, Molecular Docking and Molecular Dynamics of 3C-like Protease Inhibitors. Acta Physico-Chimica Sinca, 2016, 32(11): 2693-2708.

URL:

http://www.whxb.pku.edu.cn/10.3866/PKU.WHXB201608121     OR     http://www.whxb.pku.edu.cn/Y2016/V32/I11/2693

Fig 1 Structure of template molecule and three kinds of molecular alignment
Parameter Alignment-Ⅰ Alignment-Ⅱ Alignment-Ⅲ
CoMFA CoMSIA CoMFA CoMSIA CoMFA CoMSIA
Q2 0.101 0.522 0.277 0.178 0.437 0.186
OPN 1 9 3 2 5 1
Rncv2 0.402 0.996 0.876 0.689 0.934 0.476
Rpre2 0.553 0.904 -0.448 -0.386 -0.954 0.060
F 20.872 602.246 68.244 33.174 75.872 28.180
SEE 0.432 0.042 0.204 0.317 0.154 0.404
SEP 0.766 0.440 0.750 0.921 0.556 0.768
Field contribution/%
steric 100 16.3 100 10.1 100 12.5
electrostatic - 23.7 - 15.5 - 32.1
hydrophobic - - - - - -
H-bond donor - 40.1 - 45.2 - 31.4
H-bond acceptor - 19.9 - 29.2 - 24.0
Table 1 Summary of 3D-QSAR results
Fig 2 Ligand-based correlation plot of the predicted versus the actual pIC50 values based on the CoMSIA model
Fig 3 CoMSIA contour maps in combination with compound 1
Fig 4 Structure of compound 1
Fig 5 CoMSIA H-bond acceptor contour map in combination with compound 9
Fig 6 Interaction features of compound impacting the inhibitory effect
Fig 7 H-bond lengths between HOH523 and ligand molecules
Fig 8 Binding mode of compound 1 (orange) and the original molecule (green) docked in 3C-like protease
Fig 9 Binding mode of inhibitor compound docked in 3C-like protease
Hydrogen bond Distance/nm
docking 4YOI* 4YOG* 4YOJ*
HOH523 N―H…O 0.269 0.281 0.266 0.289
His166 N…H―N 0.290 0.287 0.288 0.286
Glu169 O…H―N 0.359 0.284 0.307 0.294
N…H―N 0.352 0.377 0.407 0.383
Table 2 H-bond lengths from docking and experiment
Fig 10 MD-simulated results of compound 1 docked in 3C-like protease
Fig 11 Plot of the in-water MD-simulated structures of the binding site
Method Donor Acceptor Distance/nm
docking His166 N ligand N 0.290
ligand N HOH523 O 0.269
Glu169 N ligand O 0.359
Glu169 N ligand N 0.352
MD Glu169 N ligand N 0.351
Glu169 N ligand O 0.293
HOH O ligand O 0.291
ligand N Ser24 O 0.340
Table 3 H-bond analysis from docking and MD simulation
Fig 12 MD-simulated results of compound 2 docked in 3C-like protease
Compound Donor Acceptor Distance/nm
1 Glu169 N ligand N 0.351
ligand N Ser24 O 0.340
HOH O ligand O 0.291
Glu169 N ligand O 0.293
2 Glu169 N ligand O 0.381
HOH O ligand O 0.270
ligand N Ser24 O 0.353
Gln192 N ligand S 0.302
Table 4 H-bond analysis from MD simulation of compound 1 and compound 2
Fig 13 Structural features of compound 1 and compound 2
Fig 14 Interaction features of peptidomimetic ligand molecule with the 3C-like protease receptor
Fig 15 Structures of newly designed molecules
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