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. 2017 Jun;89(6):1040-1047.
doi: 10.1002/jmv.24736. Epub 2017 Feb 16.

Quantitative structure-activity relationship and molecular docking revealed a potency of anti-hepatitis C virus drugs against human corona viruses

Abdo A Elfiky  1   2 , Samah M Mahdy  1   3 , Wael M Elshemey  1
Affiliations

Quantitative structure-activity relationship and molecular docking revealed a potency of anti-hepatitis C virus drugs against human corona viruses

Abdo A Elfiky et al. J Med Virol. 2017 Jun.

Abstract

A number of human coronaviruses (HCoVs) were reported in the last and present centuries. Some outbreaks of which (eg, SARS and MERS CoVs) caused the mortality of hundreds of people worldwide. The problem of finding a potent drug against HCoV strains lies in the inability of finding a drug that stops the viral replication through inhibiting its important proteins. In spite of its limited efficacy and potential side effects, Ribavirin is extensively used as a first choice against HCoVs. Therefore, scientists reverted towards the investigation of different drugs that can more specifically target proteins. In this study, four anti-HCV drugs (one approved by FDA and others under clinical trials) are tested against HCoV polymerases. Quantitative Structure-Activity Relationship (QSAR) and molecular docking are both used to compare the performance of the selected nucleotide inhibitors to their parent nucleotides and Ribavirin. Both QSAR and molecular docking showed that IDX-184 is superior compared to Ribavirin against MERS CoV, a result that was also reported for HCV. MK-0608 showed a performance that is comparable to Ribavirin. We strongly suggest an in vitro study on the potency of these two drugs against MERS CoV.

Keywords: HCV; QSAR; docking; human coronavirus; nucleotide inhibitor; polymerase.

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Figures

Figure 1
Figure 1
Sequence alignment for the 19 HCoV polymerases along with HCV NS5b RdRp (from the PDB file 2XI3). The alignment is performed using CLUSTAL omega web server and visualized using ESPript software 3.0. The conserved amino acids are highlighted in red. The active site environment amino acids (4Å around the two active site aspartates D255 and D256) are all conserved except for amino acid number 291 which is Glutamate (E) in all HCoV types other than NL63 and 229E where it is Threonine (T)
Figure 2
Figure 2
Average docking score values calculated for the HCoV (colored circles) and experimental solved HCV (diamond) polymerases. MERS and SARS CoVs are represented by large circles for clarification. The error bars represent the standard deviations of means. Docking is performed using SCIGRESS 3.0 software
Figure 3
Figure 3
3D structures of solved HCV NS5b polymerase (PDB ID 2XI3) with GTP and the docked GTP to MERS CoV selected model. Polar interactions occur in both cases with the active site amino acids (Asp318 for HCV & Asp255 and Asp256 for MERS CoV) and the active site pocket amino acids. In addition, metal interactions mediate ligand binding to the polymerases. Structures are presented using PyMOL software where proteins are represented by colored cartoon and the drugs are represented by atom colored licorice (N, blue; O, red; C, green; H, white; and P, orange)
Figure 4
Figure 4
2D ligand interaction diagrams plotted by Maestro software for the docked nucleotide inhibitors and Ribavirin into the active site pocket of MERS CoV polymerase. Major interactions are through the formation of H‐bonds (violet arrows) with the active site pocket amino acids in addition to metal interactions that stabilize the complexes. Water exposed groups (OH and NH2 groups surrounded by gray smudge) suggest water‐ligand interactions in the active site vicinity
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