Molecular dynamics simulations of ASC09, ritonavir, lopinavir and darunavir with the COVID-19 protease

Chemia Naissensis Volume 3, No.1 (2020) (стр. 155-170) 

АУТОР(И) / AUTHOR(S):  Budimir S. Ilić

Е-АДРЕСА / E-MAIL: bucabule@yahoo.com (or budimir.ilic@medfak.ni.ac.rs)

Download Full Pdf   

DOI: 10.46793/ChemN3.1.155I

САЖЕТАК / ABSTRACT:

Given the novelty of SARS-CoV-2 infection (COVID-19), and the lack of proven therapies, a wide variety of strategies are being employed to combat COVID-19 pandemic. Many of these emerging strategies rely on repurposing existing drugs and their mechanistic approaches that are effective against either similar viral infections or the serious symptoms that are caused by COVID-19. The recently solved issue of the crystal structure of the COVID-19 protease has made elucidating the structure–activity relationship feasible. The interaction of ASC09, ritonavir, lopinavir and darunavir with COVID-19 protease was simulated using the Site Finder module, molecular docking and molecular dynamics (MD). Analysis of the MD trajectories has provided the ligand/receptor interaction fingerprints, combining information on the crucial receptor residues and frequency of the ligand/residue contacts. The contact frequencies and the contact maps suggest that for all studied antiviral drugs, the interactions with Gln 107, Pro 108, Gln 110 and His 246 are an important factor for drugs affinities toward the COVID-19 protease. However, the leading interactions with Arg 105, Phe 134, Glu 240, Thr 243, Asp 245 or Phe 294 also significantly contribute to the ligand/receptor interplay and, in particular, differentiate their binding affinities toward COVID-19 protease.

КЉУЧНЕ РЕЧИ / KEYWORDS:

COVID-19, Molecular dynamics, ASC09, Ritonavir, Lopinavir, Darunavir

ЛИТЕРАТУРА / REFERENCES:

  • Ahmed, S. F., Quadeer, A. A., & McKay, M. R. (2020). Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies. Viruses, 12(3), 254.
  • ClinicalTrials (2020, July 4). U. S. National Library of Medicine, ClinicalTrials.gov. Retrieved from https://clinicaltrials.gov/ct2/results?term=Antiviral&cond=covid-19
  • Corbeil, C. R., Williams C. I., & Labute, P. (2012). Variability in docking success rates due to dataset preparation. Journal of Computer-Aided Molecular Design, 26, 775–786.
  • Desmond (2020, May 16). Desmond Molecular Dynamics System, version 2018.4, (D. E. Shaw Research, New York, NY). Retrieved from https://www.deshawresearch.com/index.html
  • Feng, H.-P., Caro, L., Fandozzi, C., Chu, X., Guo, Z., Talaty, J., Panebianco, D., Dunnington, K., Du, L., Hanley, W. D., Fraser, I. P., Mitselos, A., Denef, J.-F., Lepeleire, I. D., de Hoon, J. N., Vandermeulen, C., Marshall, W. L., Jumes, P., Huang, X., Martinho, M., Valesky, R., Butterton, J. R., Iwamoto, M., & Yeh W. W. (2019).  Pharmacokinetic  interactions  between  the  Hepatitis  C  virus  inhibitors  elbasvir  and grazoprevir and HIV protease inhibitors ritonavir, atazanavir, lopinavir, and darunavir in healthy volunteers. Antimicrobial Agents and Chemotherapy, 63(e02142-18), 1–14.
  • Haagmans, B. L., & Osterhaus, A. D. M. E. (2006). Coronaviruses and their therapy. Antiviral Research, 71, 397–403.
  • Halgren T. A. (1996). Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. Journal of Computational Chemistry, 17(5-6), 490–519.
  • Harrison, C. (2020). Coronavirus puts drug repurposing on the fast track. Nature Biotechnology, 38, 379– 381.
  • King, M. V. (1958). Improved resolution of X-ray diffraction patterns of protein crystals at low temperature. Nature, 181, 263–264.
  • Liu, K., & Kokubo, H. (2017). Exploring the stability of ligand binding modes to proteins by molecular dynamics simulations: A cross-docking study. Journal of Chemical Information and Modeling, 57, 2514– 2522.
  • MOE (2020, May 16). Molecular Operating Environment (MOE) 2019.0101, (Chemical Computing Group ULC, Montreal, QC, Canada). Retrieved from https://www.chemcomp.com/index.htm
  • Mullard, A. (2020). COVID-19 vaccines start moving into advanced trials. Nature Reviews Drug Discovery, 19, 435.
  • Owen, C. D., Lukacik, P., Strain-Damerell, C. M., Douangamath, A., Powell, A. J., Fearon, D., Brandao- Neto, J., Crawshaw, A. D., Aragao, D., Williams, M., Flaig, R., Hall, D. , McAuley, K. , Stuart, D. I., von Delft, F., & Walsh, M. A. (2020). COVID-19 main protease with unliganded active site.. RCSB Protein Data Bank (PDB) ID, 6Y84. Retrieved from https://www.rcsb.org/structure/6y84
  • Pillaiyar, T., Manickam, M., Namasivayam, V., Hayashi, Y., & Yung, S.-H. (2016). An overview of severe acute respiratory syndome-coronavirus (SARS-CoV) 3CL protease inhibitors: Peptidomimetics and small molecule chemotherapy. Journal of Medicinal Chemistry, 59, 6595–6628.
  • Protein Data Bank (2020, May 16). Retrieved from https://www.rcsb.org/
  • Ren, J.-l., Zhang, A.-H., & Wang, X.-J. (2020). Traditional Chinese medicine for COVID-19 treatment. Pharmacological Research, 155(104743), 1–2.
  • Robson, B. (2020). Computers and viral diseases. Preliminary bioinformatics studies on the design of a synthetic vaccine and a preventative peptidomimetic antagonist against the SARS-CoV-2 (2019-nCoV, COVID-19) coronavirus. Computers in Biology and Medicine, 119(103670), 1–19.
  • Sheahan, T. P., Sims, A. C., Leist, S. R., Schäfer, A., Won, J., Brown, A. J., Montgomery, S. A., Hogg, A.,
  • Babusis, D., Clarke, M. O., Spahn, J. E., Bauer, L., Sellers, S., Porter, D., Feng, J. Y., Cihlar, T., Jordan, R., Denison, M. R., & Baric, R. S. (2020). Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nature Communications, 11(222), 1–14.
  • Soga, S., Shirai, H., Kobori, M., & Hirayama, N. (2007). Use of amino acid composition to predict ligand- binding sites. Journal of Chemical Information and Modeling, 47, 400–406.
  • Wang, M., Cao, R., Zhang, L., Yang, X., Liu, J., Xu, M., Shi, Z., Hu, Z., Zhong, W., & Xiao, G. (2020). Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, 30, 269–271.
  • Worldometer (2020, July 4). COVID-19 coronavirus pandemic. Retrieved from https://www.worldometers.info/coronavirus/
  • Zhang, T., He, Y., Xu, W., Ma, A., Yang, Y., & Xu, K.-F. (2020). Clinical trials for the treatment of Coronavirus disease 2019 (COVID-19): A rapid response to urgent need. Science China Life Sciences, 63, 774-776.