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. 2024 Feb 9;10(4):e25837.
doi: 10.1016/j.heliyon.2024.e25837. eCollection 2024 Feb 29.

An in silico approach to develop potential therapies against Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

Suvro Biswas  1 , Mohasana Akter Mita  2 , Shamima Afrose  2 , Md Robiul Hasan  2 , Mst Sharmin Sultana Shimu  2 , Shahriar Zaman  1 , Md Abu Saleh  1
Affiliations

An in silico approach to develop potential therapies against Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

Suvro Biswas et al. Heliyon. .

Abstract

A deadly respiratory disease Middle East Respiratory Syndrome (MERS) is caused by a perilous virus known as MERS-CoV, which has a severe impact on human health. Currently, there is no approved vaccine, prophylaxis, or antiviral therapeutics for preventing MERS-CoV infection. Due to its inexorable and integral role in the maturation and replication of the MERS-CoV virus, the 3C-like protease is unavoidly a viable therapeutic target. In this study, 2369 phytoconstituents were enlisted from Japanese medicinal plants, and these compounds were screened against 3C-like protease to identify feasible inhibitors. The best three compounds were identified as Kihadanin B, Robustaflavone, and 3-beta-O- (trans-p-Coumaroyl) maslinic acid, with binding energies of -9.8, -9.4, and -9.2 kcal/mol, respectively. The top three potential candidates interacted with several active site residues in the targeted protein, including Cys145, Met168, Glu169, Ala171, and Gln192. The best three compounds were assessed by in silico technique to determine their drug-likeness properties, and they exhibited the least harmful features and the greatest drug-like qualities. Various descriptors, such as solvent-accessible surface area, root-mean-square fluctuation, root-mean-square deviation, hydrogen bond, and radius of gyration, validated the stability and firmness of the protein-ligand complexes throughout the 100ns molecular dynamics simulation. Moreover, the top three compounds exhibited better binding energy along with better stability and firmness than the inhibitor (Nafamostat), which was further confirmed by the binding free energy calculation. Therefore, this computational investigation could aid in the development of efficient therapeutics for life-threatening MERS-CoV infections.

Keywords: 3CLpro; ADMET; MERS-CoV; Molecular docking; Molecular dynamics simulation; Phytoconstituents.

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Conflict of interest statement

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

Fig. 1
Fig. 1
Flow chart showing the main steps of the study.
Fig. 2
Fig. 2
The red dots indicate the active site of the MERS-CoV 3CLpro protein which was retrieved from the PDBsum database. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
Fig. 3
The active sites of the MERS-CoV 3CLpro protein were retrieved from the PLIP database.
Fig. 4
Fig. 4
Two-dimensional (2D) chemical structures of (A) Kihadanin B, (B) Robustaflavone, and (C) 3-beta-O-(trans-p-Coumaroyl)maslinic acid. The structures were drawn using MarvinSketch software.
Fig. 5
Fig. 5
Different binding modes for the selected compounds within the MERS-CoV 3CLpro protein's active and catalytic sites; (A) Kihadanin B, (B) Robustaflavone, (C) 3-beta-O-(trans-p-Coumaroyl)maslinic acid.
Fig. 6
Fig. 6
Two-dimensional (2D) view of the interactions between MERS-CoV 3CLpro and the top inhibitor (Nafamostat).
Fig. 7
Fig. 7
The molecular dynamics simulation of the top three compound-MERS-CoV 3CLpro complexes along with Nafamostat-MERS-CoV 3CLpro complex, here (a) root mean square deviation of the c-alpha atoms, (b) solvent accessible surface area, (c) radius of gyration, (d) hydrogen bonding of the complexes, (e) root mean square fluctuation of the complexes.
Fig. 8
Fig. 8
The binding-free energy of the top three drugs and inhibitor complexes calculated by the MM-PBSA method.
See this image and copyright information in PMC

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