Anti-viral drug discovery against monkeypox and smallpox infection by natural curcumin derivatives: A Computational drug design approach

Abstract

Background: In the last couple of years, viral infections have been leading the globe, considered one of the most widespread and extremely damaging health problems and one of the leading causes of mortality in the modern period. Although several viral infections are discovered, such as SARS CoV-2, Langya Henipavirus, there have only been a limited number of discoveries of possible antiviral drug, and vaccine that have even received authorization for the protection of human health. Recently, another virial infection is infecting worldwide (Monkeypox, and Smallpox), which concerns pharmacists, biochemists, doctors, and healthcare providers about another epidemic. Also, currently no specific treatment is available against Monkeypox. This research gap encouraged us to develop a new molecule to fight against monkeypox and smallpox disease. So, firstly, fifty different curcumin derivatives were collected from natural sources, which are available in the PubChem database, to determine antiviral capabilities against Monkeypox and Smallpox.

Material and method: Preliminarily, the molecular docking experiment of fifty different curcumin derivatives were conducted, and the majority of the substances produced the expected binding affinities. Then, twelve curcumin derivatives were picked up for further analysis based on the maximum docking score. After that, the density functional theory (DFT) was used to determine chemical characterizations such as the highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), softness, and hardness, etc.

Results: The mentioned derivatives demonstrated docking scores greater than 6.80 kcal/mol, and the most significant binding affinity was at -8.90 kcal/mol, even though 12 molecules had higher binding scores (-8.00 kcal/mol to -8.9 kcal/mol), and better than the standard medications. The molecular dynamic simulation is described by root mean square deviation (RMSD) and root-mean-square fluctuation (RMSF), demonstrating that all the compounds might be stable in the physiological system.

Conclusion: In conclusion, each derivative of curcumin has outstanding absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics. Hence, we recommended the aforementioned curcumin derivatives as potential antiviral agents for the treatment of Monkeypox and Smallpox virus, and more in vivo investigations are warranted to substantiate our findings.

Keywords: DFT; admet; curcumin; molecular docking; molecular dynamic simulation; monkeypox; smallpox virus.

Figure 1

Physiological structures of MPXV.

Figure 2

Optimized structure of curcumin derivatives.

Figure 3

Chemical structure of curcumin and its derivatives.

Figure 4

Probable mechanism action of curcumin against the virus.

Figure 5

Monkeypox transmission pathway.

Figure 6

Experimental three-dimensional protein structures information (Minasov et al., 2022; Perry et al., 2010).

Figure 7

Molecular docking pocket, hydrogen bonding, and binding interaction. (A) Docking pocket, (B) Active side (Amino acid residues), (C) Ionizibility.

Figure 8

HOMO and LUMO diagram of curcumin and its derivatives.

Figure 9

The RMSD of Cα atoms over time for proteins and ligands. Here, red and violet lines denote compound 42 and Acyclovir complexes, respectively.

Figure 10

The structural behavior change of protein by means of (A) solvent accessible surface area (SASA), (B) radius of gyration, and (C) root means square fluctuations (RMSF) analysis. Here, the red line indicates Acyclovir, and the violet line indicates compound 42 complexes, respectively.

Figure 11

The number of hydrogen bonds created overall between protein-ligand complexes via MD simulations. Here, the red line indicates Acyclovir complexes, and violet lines indicate compound 42 complexes, respectively.