Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Feb 19;24(2):102021.
doi: 10.1016/j.isci.2020.102021. Epub 2021 Jan 5.

A multi-pronged approach targeting SARS-CoV-2 proteins using ultra-large virtual screening

Christoph Gorgulla  1   2   3 , Krishna M Padmanabha Das  1   3 , Kendra E Leigh  4 , Marco Cespugli  5 , Patrick D Fischer  1   3   6 , Zi-Fu Wang  1 , Guilhem Tesseyre  7 , Shreya Pandita  7 , Alec Shnapir  7 , Anthony Calderaio  8 , Minko Gechev  7 , Alexander Rose  9 , Noam Lewis  7 , Colin Hutcheson  7 , Erez Yaffe  7 , Roni Luxenburg  7 , Henry D Herce  1   3 , Vedat Durmaz  5 , Thanos D Halazonetis  10 , Konstantin Fackeldey  11   12 , J J Patten  13 , Alexander Chuprina  14 , Igor Dziuba  15 , Alla Plekhova  16 , Yurii Moroz  16   17 , Dmytro Radchenko  14   17 , Olga Tarkhanova  16 , Irina Yavnyuk  14 , Christian Gruber  5   18 , Ryan Yust  7 , Dave Payne  7 , Anders M Näär  19 , Mark N Namchuk  1 , Robert A Davey  13 , Gerhard Wagner  1 , Jamie Kinney  7 , Haribabu Arthanari  1   3
Affiliations

A multi-pronged approach targeting SARS-CoV-2 proteins using ultra-large virtual screening

Christoph Gorgulla et al. iScience. .

Abstract

The unparalleled global effort to combat the continuing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic over the last year has resulted in promising prophylactic measures. However, a need still exists for cheap, effective therapeutics, and targeting multiple points in the viral life cycle could help tackle the current, as well as future, coronaviruses. Here, we leverage our recently developed, ultra-large-scale in silico screening platform, VirtualFlow, to search for inhibitors that target SARS-CoV-2. In this unprecedented structure-based virtual campaign, we screened roughly 1 billion molecules against each of 40 different target sites on 17 different potential viral and host targets. In addition to targeting the active sites of viral enzymes, we also targeted critical auxiliary sites such as functionally important protein-protein interactions.

Keywords: Drugs; High-Performance Computing in Bioinformatics; Structural Biology; Virology.

PubMed Disclaimer

Conflict of interest statement

M.C. and V.D. report working for Innophore. C.C.G. reports being a shareholder and CEO of Innophore, an enzyme and drug discovery company. G.W. and C.G. report being co-founders of the company Virtual Discovery, Inc., which provides virtual screening services. G.W. reports serving as the director of this company. G.W. reports being a co-founder of PIC Therapeutics, Cellmig Biolabs, and Skinap Therapeutics. H.A. reports being an equity holder in PIC Therapeutics. I.I. and D.R. report working for Enamine, a company that is involved in the synthesis and distribution of chemical building blocks, fragments, and screening compounds. Y.M. reports being a scientific advisor for Enamine. Y.M., O.T., and A.P. report working for Chemspace, a company that is involved in the distribution of chemical building blocks, fragments, and screening compounds. I.D. reports working for UkrOrgSyntez Ltd. (UORSY), a company that is involved in the synthesis of chemical building blocks, fragments, and screening compounds. G.T., S.P., A.S., M.G., N.L., C.H., E.Y., R.L., R.Y., D.P., and J.K. report working for Google, a company that also provides cloud computing services. The research described here is scientifically and financially independent of the efforts in any of the above mentioned companies.

Figures

None
Graphical abstract
Figure 1
Figure 1
Schematic of the viral life cycle of SARS-CoV-2 The genome organization is based on other coronaviruses and published predictions (Snijder et al., 2016; Wu et al., 2020). ACE2: angiotensin-converting enzyme 2; TMPRSS2: transmembrane protease, serine 2; RdRp: RNA-dependent RNA polymerase; ExoN: exonuclease; N7-MT N7-methyltransferase; 2′O-MTase: 2′O-methyltransferase; EndoU: uridylate-specific endonuclease; RTC: replication and transcription complex; ER: endoplasmic reticulum; TGN: trans-Golgi network.
Figure 2
Figure 2
The ACE2 receptor and an example compound from the top 0.0001% of screened compounds bound at the spike interaction interface (site1) (A) The target protein ACE2 (gold) bound to the RBD of the spike protein (magenta) and an example compound (light pink) from the virtual screen bound to the spike interaction interface (site 1, around Glu37) (screen ID: 1). (B) The electrostatic surface of the target protein (ACE2) bound to the RBD domain of the spike protein (magenta) and an example compound (light pink). (C) An overview of the interactions between the ligand and the receptor structure. (D) Receptor residues within 4 Å of the ligand. (E) Distribution of the docking scores of the top 100 virtual screening hits.
Figure 3
Figure 3
The helicase (nsp13) and an example compound from the top 0.0001% of screened compounds bound at site 2 of the RNA binding interface (A) The helicase (violet) bound to an example compound (light pink) at region 2 of the RNA binding interface. A docked DNA strand is shown in light gold (screen ID: 35). (B) Electrostatic surface of the helicase to which an example compound (light pink) and a docked DNA strand (light gold) are bound. (C) An overview of the interactions between the compound and the helicase structure. (D) Residues within 4 Å of the inhibitor. (E) Distribution of the docking scores of the top 100 virtual screening hits.
Figure 4
Figure 4
The phosphatase (closed conformation) and an example compound from the top 0.0001% of screened compounds bound at the enzymatic active site (A) The phosphatase (violet), which is part of nsp3, and an example compound (light pink) from the virtual screen bound to the active site (closed conformation) (screen ID: 10). (B) Electrostatic surface of the target protein to which an example compound (light pink) is bound. (C) An overview of the interactions between the inhibitor and the phosphatase structure. (D) Residues within 4 Å of the inhibitor. (E) Distribution of the docking scores of the top 100 virtual screening hits.
See this image and copyright information in PMC

Update of

References

    1. Adedeji A.O., Marchand B., te Velthuis A.J.W., Snijder E.J., Weiss S., Eoff R.L., Singh K., Sarafianos S.G. Mechanism of nucleic acid unwinding by SARS-CoV helicase. PLoS One. 2012;7:e36521. doi: 10.1371/journal.pone.0036521. - DOI - PMC - PubMed
    1. Afar D.E., Vivanco I., Hubert R.S., Kuo J., Chen E., Saffran D.C., Raitano A.B., Jakobovits A. Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia. Cancer Res. 2001;61:1686–1692. - PubMed
    1. Agostini M.L., Andres E.L., Sims A.C., Graham R.L., Sheahan T.P., Lu X., Smith E.C., Case J.B., Feng J.Y., Jordan R. Coronavirus susceptibility to the antiviral Remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio. 2018;9 doi: 10.1128/mBio.00221-18. - DOI - PMC - PubMed
    1. Agostini M.L., Pruijssers A.J., Chappell J.D., Gribble J., Lu X., Erica L.A., Bluemling G.R., Lockwood M.A., Sheahan T.P., Sims A.C., Natchus M.G. Small-molecule antiviral β-d-n4-hydroxycytidine inhibits a proofreading-intact coronavirus with a high genetic barrier to resistance. J. Virol. 2019;93 doi: 10.1128/jvi.01348-19. - DOI - PMC - PubMed
    1. Allison L.T., Bavari S. Broad-spectrum coronavirus antiviral drug discovery. Expert Opin. Drug Discov. 2019;14:397–412. doi: 10.1080/17460441.2019.1581171. - DOI - PMC - PubMed