TY - JOUR
T1 - Inhibition mechanism and hot-spot prediction of nine potential drugs for SARS-CoV-2 Mproby large-scale molecular dynamic simulations combined with accurate binding free energy calculations
AU - Luo, Song
AU - Huang, Kaifang
AU - Zhao, Xiaoyu
AU - Cong, Yalong
AU - Zhang, John Z.H.
AU - Duan, Lili
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (grant no. 11774207, 11574184, 91753103, and 21933010), National Key R&D Program of China (grant no. 2016YFA0501700), and NYU Global Seed Grant. We thank the ECNU Public Platform for Innovation 001 for providing supercomputer time.
Publisher Copyright:
© The Royal Society of Chemistry.
PY - 2021/5/7
Y1 - 2021/5/7
N2 - Coronavirus disease 2019 (COVID-19), which is caused by a new coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading around the world. However, a universally effective treatment regimen has not been developed to date. The main protease (Mpro), a key enzyme of SARS-CoV-2, plays a crucial role in the replication and transcription of this virus in cells and has become the ideal target for rational antiviral drug design. In this study, we performed molecular dynamics simulations three times for these complexes of Mpro (monomeric and dimeric) and nine potential drugs that have a certain effect on the treatment of COVID-19 to explore their binding mechanism. In addition, a total of 12 methods for calculating binding free energy were employed to determine the optimal drug. Ritonavir, Arbidol, and Chloroquine consistently showed an outstanding binding ability to monomeric Mpro under various methods. Ritonavir, Arbidol, and Saquinavir presented the best performance when binding to a dimer, which was independent of the protonated state of Hie41 (protonated at Nϵ) and Hid41 (protonated at Nδ), and these findings suggest that Chloroquine may not effectively inhibit the activity of dimeric Mproin vivo. Furthermore, three common hot-spot residues of Met165, Hie41, and Gln189 of monomeric Mpro systems dominated the binding of Ritonavir, Arbidol, and Chloroquine. In dimeric Mpro, Gln189, Met165, and Met49 contributed significantly to binding with Ritonavir, Arbidol, and Saquinavir; therefore, Gln189 and Met165 might serve as the focus in the discovery and development of anti-COVID-19 drugs. In addition, the van der Waals interaction played a significant role in the binding process, and the benzene ring of the drugs showed an apparent inhibitory effect on the normal function of Mpro. The binding cavity had great flexibility to accommodate these different drugs. The results would be notably helpful for enabling a detailed understanding of the binding mechanisms for these important drug-Mpro interactions and provide valuable guidance for the design of potent inhibitors.
AB - Coronavirus disease 2019 (COVID-19), which is caused by a new coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading around the world. However, a universally effective treatment regimen has not been developed to date. The main protease (Mpro), a key enzyme of SARS-CoV-2, plays a crucial role in the replication and transcription of this virus in cells and has become the ideal target for rational antiviral drug design. In this study, we performed molecular dynamics simulations three times for these complexes of Mpro (monomeric and dimeric) and nine potential drugs that have a certain effect on the treatment of COVID-19 to explore their binding mechanism. In addition, a total of 12 methods for calculating binding free energy were employed to determine the optimal drug. Ritonavir, Arbidol, and Chloroquine consistently showed an outstanding binding ability to monomeric Mpro under various methods. Ritonavir, Arbidol, and Saquinavir presented the best performance when binding to a dimer, which was independent of the protonated state of Hie41 (protonated at Nϵ) and Hid41 (protonated at Nδ), and these findings suggest that Chloroquine may not effectively inhibit the activity of dimeric Mproin vivo. Furthermore, three common hot-spot residues of Met165, Hie41, and Gln189 of monomeric Mpro systems dominated the binding of Ritonavir, Arbidol, and Chloroquine. In dimeric Mpro, Gln189, Met165, and Met49 contributed significantly to binding with Ritonavir, Arbidol, and Saquinavir; therefore, Gln189 and Met165 might serve as the focus in the discovery and development of anti-COVID-19 drugs. In addition, the van der Waals interaction played a significant role in the binding process, and the benzene ring of the drugs showed an apparent inhibitory effect on the normal function of Mpro. The binding cavity had great flexibility to accommodate these different drugs. The results would be notably helpful for enabling a detailed understanding of the binding mechanisms for these important drug-Mpro interactions and provide valuable guidance for the design of potent inhibitors.
KW - Antiviral Agents/pharmacology
KW - COVID-19
KW - Cysteine Endopeptidases/metabolism
KW - Humans
KW - Molecular Docking Simulation
KW - Molecular Dynamics Simulation
KW - Pharmaceutical Preparations
KW - SARS-CoV-2
KW - Viral Nonstructural Proteins
UR - http://www.scopus.com/inward/record.url?scp=85105664928&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85105664928&partnerID=8YFLogxK
U2 - 10.1039/d0nr07833f
DO - 10.1039/d0nr07833f
M3 - Article
C2 - 33900318
AN - SCOPUS:85105664928
SN - 2040-3364
VL - 13
SP - 8313
EP - 8332
JO - Nanoscale
JF - Nanoscale
IS - 17
ER -