Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants

Abstract

The recent pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has raised global health concerns. The viral 3-chymotrypsin-like cysteine protease (3CL^pro) enzyme controls coronavirus replication and is essential for its life cycle. 3CL^pro is a proven drug discovery target in the case of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Recent studies revealed that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV. Therefore, herein, we analysed the 3CL^pro sequence, constructed its 3D homology model, and screened it against a medicinal plant library containing 32,297 potential anti-viral phytochemicals/traditional Chinese medicinal compounds. Our analyses revealed that the top nine hits might serve as potential anti- SARS-CoV-2 lead molecules for further optimisation and drug development process to combat COVID-19.

Keywords: COVID-19; Coronavirus; Molecular docking; Molecular dynamics simulation; Natural products; Protein homology modelling; SARS-CoV-2.

Graphical abstract

Fig. 1

(A) Phylogenetic tree inferred from closest homologs of SARS-CoV-2 3CL^pro. The maximum likelihood method was used to construct this tree. (B) Multiple sequence alignment of closest homologs of SARS-CoV-2 3CL^pro sharing ≥70% sequence identity. (C) Cartoon representation of the SARS-CoV-2 3CL^pro homodimer. Chain-A (protomer-A) is in multicolour and Chain-B (protomer-B) is in dark blue. The N-finger that plays an important role in dimerization maintaining the active conformation is shown in hot pink, domain I is coloured cyan, domain II is shown in green, and domain III is coloured yellow. The N- and C-termini are labelled. Residues of the catalytic dyad (Cys-145 and His-41) are highlighted in yellow and labelled. (D) Cartoon representation of the 3CL^pro monomer model (chain/protomer-A) of SARS-CoV-2 superimposed with the SARS-CoV 3CL^pro structure. The SARS-CoV 3CL^pro template is coloured cyan, the SARS-CoV-2 3CL^pro structure is coloured grey, and all identified mutations are highlighted in red. (E) Docking of 5,7,3′,4′-tetrahydroxy-2’-(3,3-dimethylallyl) isoflavone inside the receptor-binding site of SARS-CoV-2 3CL^pro, showing hydrogen bonds with the catalytic dyad (Cys-145 and His-41). The 3CL^pro structure is coloured dark blue, the 5,7,3′,4′-tetrahydroxy-2’-(3,3-dimethylallyl) isoflavone is orange, and hydrogen coloured maroon.

Fig. 2

(A) Root mean square deviation (RMSD), (B) root mean square fluctuation (RMSF), (C) potential energy and (D) Hydrogen Bond interactions for all three complexes over the 50 ns simulation.