Potential therapeutic target identification in the novel 2019 coronavirus: insight from homology modeling and blind docking study

Abstract

Background: The 2019-nCoV which is regarded as a novel coronavirus is a positive-sense single-stranded RNA virus. It is infectious to humans and is the cause of the ongoing coronavirus outbreak which has elicited an emergency in public health and a call for immediate international concern has been linked to it. The coronavirus main proteinase which is also known as the 3C-like protease (3CLpro) is a very important protein in all coronaviruses for the role it plays in the replication of the virus and the proteolytic processing of the viral polyproteins. The resultant cytotoxic effect which is a product of consistent viral replication and proteolytic processing of polyproteins can be greatly reduced through the inhibition of the viral main proteinase activities. This makes the 3C-like protease of the coronavirus a potential and promising target for therapeutic agents against the viral infection.

Results: This study describes the detailed computational process by which the 2019-nCoV main proteinase coding sequence was mapped out from the viral full genome, translated and the resultant amino acid sequence used in modeling the protein 3D structure. Comparative physiochemical studies were carried out on the resultant target protein and its template while selected HIV protease inhibitors were docked against the protein binding sites which contained no co-crystallized ligand.

Conclusion: In line with results from this study which has shown great consistency with other scientific findings on coronaviruses, we recommend the administration of the selected HIV protease inhibitors as first-line therapeutic agents for the treatment of the current coronavirus epidemic.

Keywords: Coronavirus; Inhibitors; Ligand; Proteinase; Replication.

Fig. 1

Dimeric crystal structure of the SARS coronavirus main proteinase (source https://www.rcsb.org/3d-view/1UJ1/1)

Fig. 2

Translated region of the 2019-nCoV nucleotide sequence with the full sequence forming the target protein coding sequence

Fig. 3

3D structures of the target and template protein, with the structural comparison. The target protein is represented at the top left region in grey color (a), while the template is on the top right in light blue color (b). The matching together of the two was depicted in the mixed color picture beneath (c)

Fig. 4

Sequence alignment between the amino acid sequence of the target protein and the SARS coronavirus main proteinase

Fig. 5

Sequence alignment between the nucleotide sequence of the back-translated SARS coronavirus main proteinase and the 10055 to 10972 nucleotide region of the 2019-nCoV complete genome

Fig. 6

Local quality estimate graph showing the values of the predicted local similarity to target (y-axis) plotted against the protein residue number (x-axis). This quality estimation was carried out on both chains of the target protein with the red and blue lines representing chains A and B, respectively

Fig. 7

Graphical presentation of estimation of absolute quality of the target protein

Fig. 8

Depicted here are two Ramachandran plots. The plot on the left hand side shows the general torsion angles for all the residues in the target protein while the plot on the right hand side is specific for the glycine residues of the protein

Fig. 9

The target protein secondary structures with bound lopinavir. At the top is the secondary structure visualization on pymol with regions making up the alpha helix, beta sheets, and loops shown in light blue, purple, and brown, respectively. Below is the prediction by CFSSP where the red, green, yellow, and blue lines depict regions of the helices, sheets, turns, and coils (loops), respectively. The predicted secondary structure composition shows a high degree of alpha helix and beta sheets, respectively, occupying 45 and 47% of the total residues with the percentage loop occupancy at 8%

Fig. 10

Bootstrap consensus phylogenetic tree

Fig. 11

a, c The induced fit binding of lopinavir and ritonavir respectively to the target protein active site while b and d show their respective 2D structures

Fig. 12

The polar interaction of lopinavir (a) and ritonavir (b) when bound to the active site of the downloaded 3D structure of the SARS-CoV main proteinase (6m2n). The compounds are colored predominantly in green (according to elements) for each column and bound to the active site residues displayed in a zoomed ribbon form and colored according to secondary structures (regions of helix, sheets, and coils colored in blue, purple, and brown, respectively)

Fig. 13

Amino acid residues forming the target protein active site