Identification of Potential TMPRSS2 Inhibitors for COVID-19 Treatment in Chinese Medicine by Computational Approaches and Surface Plasmon Resonance Technology

Background:
Coronavirus disease-19 (COVID-19) pneumonia
continues
to spread in the entire globe with limited medication available. In
this study, the active compounds in Chinese medicine (CM) recipes
targeting the transmembrane serine protease 2 (TMPRSS2) protein for
the treatment of COVID-19 were explored. Methods: The conformational
structure of TMPRSS2 protein (TMPS2) was built through homology modeling.
A training set covering TMPS2 inhibitors and decoy molecules was docked
to TMPS2, and their docking poses were re-scored with scoring schemes.
A receiver operating characteristic (ROC) curve was applied to select
the best scoring function. Virtual screening of the candidate compounds
(CCDs) in the six highly effective CM recipes against TMPS2 was conducted
based on the validated docking protocol. The potential CCDs after
docking were subject to molecular dynamics (MD) simulations and surface
plasmon resonance (SPR) experiment. Results: A training set of 65
molecules were docked with modeled TMPS2 and LigScore2 with the highest
area under the curve, AUC, value (0.886) after ROC analysis selected
to best differentiate inhibitors from decoys. A total of 421 CCDs
in the six recipes were successfully docked into TMPS2, and the top
16 CCDs with LigScore2 higher than the cutoff (4.995) were screened
out. MD simulations revealed a stable binding between these CCDs and
TMPS2 due to the negative binding free energy. Lastly, SPR experiments
validated the direct combination of narirutin, saikosaponin B1, and
rutin with TMPS2. Conclusions: Specific active compounds including
narirutin, saikosaponin B1, and rutin in CM recipes potentially target
and inhibit TMPS2, probably exerting a therapeutic effect on COVID-19.