Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
General Research Article

Molecular Dynamics and Inhibition of MERS CoV Papain-like Protease by Small Molecule Imidazole and Aminopurine Derivatives

Author(s): Mahmoud Kandeel*, Abdallah Altaher and Mohamed Alnazawi

Volume 16, Issue 5, 2019

Page: [584 - 591] Pages: 8

DOI: 10.2174/1570180815666180918161922

Price: $65

Abstract

Background: Middle East Respiratory Syndrome coronavirus (MERS CoV) is a newly emerged viral disease with a fatal outcome.

Methods: During the search for new antiviral drugs, MERS CoV papain-like protease (Plpro) was identified as a possible target. In this work, MERS CoV Plpro was investigated by virtual screening, enzyme inhibition and molecular dynamics to find new inhibitors. After the virtual screening of a dataset of small molecules, 5 compounds were selected for inhibitory studies.

Results: Purine and imidazole-pyridine derivatives were identified as MERS CoV Plpro inhibitors with Ki values of 73 and 68 µM, respectively. The binding of inhibitors showed marked changes in both the fingers subdomain and Ubl domain, with negligible changes in the catalytic domain. The binding of inhibitors was associated with the formation of favorable hydrogen bonds with the side chains of Plpro S1648 or Y1760.

Conclusion: Further optimization of the present set can lead to more potent inhibitors through the design of small molecules with improved binding affinity.

Keywords: Coronavirus, protease, inhibitors, MERS CoV, Plpro, molecular dynamics.

« Previous Next »
Graphical Abstract

[1]
Zaki, A.M.; Van Boheemen, S.; Bestebroer, T.M.; Osterhaus, A.D.; Fouchier, R.A. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. New . Eng. J. Med., 2012, 367(19), 1814-1820.
[2]
Kandeel, M.; Elaiziz, M.; Kandeel, A.; Altaher, A.; Kitade, Y. Association of host tropism of Middle East syndrome coronavirus with the amino acid structure of host cell receptor dipeptidyl peptidase 4. Acta Virol., 2013, 58(4), 359-363.
[3]
Reusken, C.B.; Messadi, L.; Feyisa, A.; Ularamu, H.; Godeke, G.J.; Danmarwa, A.; Dawo, F.; Jemli, M.; Melaku, S.; Shamaki, D. Geographic distribution of MERS coronavirus among dromedary camels, Africa. Emerg. Infec. Dis., 2014, 20(8), 1370-1374.
[4]
Devi, J.P.; Noraini, W.; Norhayati, R.; Kheong, C.C.; Badrul, A.; Zainah, S.; Fadzilah, K.; Hirman, I.; Hakim, S.L.; Hisham, A.N. Laboratory-confirmed case of Middle East respiratory syndrome coronavirus (MERS-CoV) infection in Malaysia: Preparedness and response. Euro Surveill., 2014, 19(18), pii20797.
[5]
Su, S.; Wong, G.; Liu, Y.; Gao, G.F.; Li, S.; Bi, Y. MERS in South Korea and China: A potential outbreak threat? Lancet, 2015, 385(9985), 2349-2350.
[6]
Shi, J.; Zhang, J.; Li, S.; Sun, J.; Teng, Y.; Wu, M.; Li, J.; Li, Y.; Hu, N.; Wang, H. Epitope-based vaccine target screening against highly pathogenic MERS-CoV: An in silico approach applied to emerging infectious diseases. PloS One, 2015, 10(12), e0144475.
[7]
Lee, H.; Lei, H.; Santarsiero, B.D.; Gatuz, J.L.; Cao, S.; Rice, A.J.; Patel, K.; Szypulinski, M.Z.; Ojeda, I.; Ghosh, A.K. Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV. ACS Chem. Biol., 2015, 10(6), 1456-1465.
[8]
Wang, F.; Chen, C.; Tan, W.; Yang, K.; Yang, H. Structure of main protease from human coronavirus NL63: Insights for wide spectrum anti-coronavirus drug design. Sci. Rep., 2016, 6, 22677.
[9]
Wu, A.; Wang, Y.; Zeng, C.; Huang, X.; Xu, S.; Su, C.; Wang, M.; Chen, Y.; Guo, D. Prediction and biochemical analysis of putative cleavage sites of the 3C-like protease of Middle East respiratory syndrome coronavirus. Virus Res., 2015, 208, 56-65.
[10]
Lei, J.; Hilgenfeld, R. Structural and mutational analysis of the interaction between the Middle-East respiratory syndrome coronavirus (MERS-CoV) papain-like protease and human ubiquitin. Virol. Sin., 2016, 31, 288-299.
[11]
Mielech, A.M.; Kilianski, A.; Baez-Santos, Y.M.; Mesecar, A.D.; Baker, S.C. MERS-CoV papain-like protease has deISGylating and deubiquitinating activities. Virology, 2014, 450, 64-70.
[12]
Lin, M-H.; Chuang, S-J.; Chen, C-C.; Cheng, S-C.; Cheng, K-W.; Lin, C-H.; Sun, C-Y.; Chou, C-Y. Structural and functional characterization of MERS coronavirus papain-like protease. J. Biomed. Sci., 2014, 21(1), 1.
[13]
Cheng, K-W.; Cheng, S-C.; Chen, W-Y.; Lin, M-H.; Chuang, S-J.; Cheng, I-H.; Sun, C-Y.; Chou, C-Y. Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res., 2015, 115, 9-16.
[14]
Kandeel, M.; Altaher, A.; Kitade, Y.; Abdelaziz, M.; Alnazawi, M.; Elshazli, K. Evolution of camel CYP2E1 and its associated power of binding toxic industrial chemicals and drugs. Comput. Biol. Chem., 2016, 64, 271-280.
[15]
Kandeel, M.; Kitade, Y. Computational analysis of siRNA recognition by the Ago2 PAZ domain and identification of the determinants of RNA-induced gene silencing. PloS One, 2013, 8, e57140.
[16]
Kandeel, M.; Kitade, Y. In silico molecular docking analysis of the human Argonaute 2 PAZ domain reveals insights into RNA interference. J. Comp. Aided Mol. Des., 2013, 27(7), 605-614.
[17]
Kandeel, M.; Ando, T.; Kitamura, Y.; Abdel-Aziz, M.; Kitade, Y. Mutational, inhibitory and microcalorimetric analyses of Plasmodium falciparum TMP kinase. Implications for drug discovery. Parasitology, 2009, 136(01), 11-25.
[18]
Altaher, Y.; Kandeel, M. Molecular analysis of some camel cytochrome P450 enzymes reveals lower evolution and drug-binding properties. J. Biomol. Struct. Dynamics., 2016, 34(1), 115-124.
[19]
Altaher, Y.; Nakanishi, M.; Kandeel, M. Annotation of camel genome for estimation of drug binding power, evolution and adaption of cytochrome P450 1a2. Int. J. Pharmacol., 2015, 11(3), 243-247.
[20]
Krieger, E.; Koraimann, G.; Vriend, G. Increasing the precision of comparative models with YASARA NOVA-a self‐parameterizing force field. Proteins: Struct. Func. Bioinform., 2002, 47(3), 393-402.
[21]
Alfuwaires, M.; Altaher, A.; Kandeel, M. Molecular Dynamic studies of interferon and innate immunity resistance in MERS CoV non-structural protein 3. Biol. Pharmaceut . Bull., 2017, 40(3), 345-351.
[22]
Clasman, J.R.; Báez-Santos, Y.M.; Mettelman, R.C.; O’Brien, A.; Baker, S.C.; Mesecar, A.D. X-ray structure and enzymatic activity profile of a core papain-like protease of MERS coronavirus with utility for structure-based drug design. Scient. Rep., 2017, 7, 40292.

Rights & Permissions Print Cite
Article Metrics
36
7
1
1
© 2024 Bentham Science Publishers | Privacy Policy