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. 2020 Nov:100:107710.
doi: 10.1016/j.jmgm.2020.107710. Epub 2020 Aug 11.

Structural analysis of experimental drugs binding to the SARS-CoV-2 target TMPRSS2

David J Huggins  1
Affiliations

Structural analysis of experimental drugs binding to the SARS-CoV-2 target TMPRSS2

David J Huggins. J Mol Graph Model. 2020 Nov.

Abstract

The emergence of SARS-CoV-2 has prompted a worldwide health emergency. There is an urgent need for therapeutics, both through the repurposing of approved drugs and the development of new treatments. In addition to the viral drug targets, a number of human drug targets have been suggested. In theory, targeting human proteins should provide an advantage over targeting viral proteins in terms of drug resistance, which is commonly a problem in treating RNA viruses. This paper focuses on the human protein TMPRSS2, which supports coronavirus life cycles by cleaving viral spike proteins. The three-dimensional structure of TMPRSS2 is not known and so we have generated models of the TMPRSS2 in the apo state as well as in complex with a peptide substrate and putative inhibitors to aid future work. Importantly, many related human proteases have 80% or higher identity with TMPRSS2 in the S1-S1' subsites, with plasminogen and urokinase-type plasminogen activator (uPA) having 95% identity. We highlight 376 approved, investigational or experimental drugs targeting S1A serine proteases that may also inhibit TMPRSS2. Whilst the presence of a relatively uncommon lysine residue in the S2/S3 subsites means that some serine protease inhibitors will not inhibit TMPRSS2, this residue is likely to provide a handle for selective targeting in a focused drug discovery project. We discuss how experimental drugs targeting related serine proteases might be repurposed as TMPRSS2 inhibitors to treat coronaviruses.

Keywords: Drug design; Homology modelling; Molecular modelling; SARS-CoV-2; Serine protease; TMPRSS2.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Sequence alignment between the serine protease domains of TMPRSS2 and TMPRSS15. The loop regions that were remodelled are highlighted by green bars. TMPRSS2 residues in the S4–S3–S2–S1–S1′-S2′-S3′-S4′ subsites are colored red. TMPRSS2 residues in the S1–S1′ subsites are further highlighted in bold. The lysine residue between the S2/S3 subsites is highlighted with a blue arrow. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article).
Fig. 2
Fig. 2
The RMSD of the protein alpha carbons relative to the original structure (blue) and the RMSD of the ligand relative to the original structure (red) across the 100 ns simulation. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article).
Fig. 3
Fig. 3
Predicted structure of the SARS-CoV-2 S2′ cleavage site sequence PSKRSFIE bound to the homology model of TMPRS22. The TMPRSS2 protein is displayed as green ribbons with atoms in green wire. The peptide is displayed as cyan balls and sticks. Residues within 4 Ångström of the S1–S1′ sites are displayed as red space filling. Residues within 4 Ångström of the S4–S3–S2–S1–S1′-S2′-S3′-S4′ sites are displayed as orange sticks. The eight subsites and residue Lys392 are denoted. The homology model of TMPRS22 overlaid with the SARS-CoV-2 S2′ cleavage site PSKRSFIE 8-mer is available on Github: https://github.com/djhuggins/TMPRSS2/blob/master/HomologyModels/TMPRSS2_HomologyModelFrom4DGJ_SubstrateOverlay.pdb. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article).
Fig. 4
Fig. 4
Putative model of TMPRSS2 bound to the experimental drugs from (a) Trypsin in PDBID 1GHV [33], (b) uPA in PDBID 1SQA [34], (c) uPA in PDBID 2VIV [35], (d) factor VII in PDBID 2FLR [36], (e) uPA in PDBID 1EJN [37], (f) uPA in PDBID 1OWH [38], (g) hepsin in PDBID 1O5E [39], and (h) uPA in PDBID 1GJC [40]. The TMPRSS2 protein is displayed as green ribbons with atoms in green wire and the predicted binding modes of the experimental drugs in TMPRSS2 are shown in green balls and sticks. The experimental protein structures are displayed as different colored ribbons with wire atoms and the binding modes of the experimental drugs are shown as balls and sticks. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
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