In silico study on anti-Chikungunya virus activity of hesperetin.
BACKGROUND
The re-emerging,Aedes spp.transmitted Chikungunya virus (CHIKV) has recently caused large outbreaks in a wide geographical distribution of the world including countries in Europe and America. Though fatalities associated with this self-remitting disease were rarely reported, quality of patients' lives have been severely diminished by polyarthralgia recurrence. Neither effective antiviral treatment nor vaccines are available for CHIKV. Our previous in vitro screening showed that hesperetin, a bioflavonoid exhibits inhibitory effect on the virus intracellular replication. Here, we present a study using the computational approach to identify possible target proteins for future mechanistic studies of hesperetin.


METHODS
3D structures of CHIKV nsP2 (3TRK) and nsP3 (3GPG) were retrieved from Protein Data Bank (PDB), whereas nsP1, nsP4 and cellular factor SPK2 were modeled using Iterative Threading Assembly Refinement (I-TASSER) server based on respective amino acids sequence. We performed molecular docking on hesperetin against all four CHIKV non-structural proteins and SPK2. Proteins preparation and subsequent molecular docking were performed using Discovery Studio 2.5 and AutoDock Vina 1.5.6. The Lipinski's values of the ligand were computed and compared with the available data from PubChem. Two non-structural proteins with crystal structures 3GPG and 3TRK in complexed with hesperetin, demonstrated favorable free energy of binding from the docking study, were further explored using molecular dynamics (MD) simulations.


RESULTS
We observed that hesperetin interacts with different types of proteins involving hydrogen bonds, pi-pi effects, pi-cation bonding and pi-sigma interactions with varying binding energies. Among all five tested proteins, our compound has the highest binding affinity with 3GPG at -8.5 kcal/mol. The ligand used in this study also matches the Lipinski's rule of five in addition to exhibiting closely similar properties with that of in PubChem. The docking simulation was performed to obtain a first guess of the binding structure of hesperetin complex and subsequently analysed by MD simulations to assess the reliability of the docking results. Root mean square deviation (RMSD) of the simulated systems from MD simulations indicated that the hesperetin complex remains stable within the simulation timescale.


CONCLUSIONS
The ligand's tendencies of binding to the important proteins for CHIKV replication were consistent with our previous in vitro screening which showed its efficacy in blocking the virus intracellular replication. NsP3 serves as the highest potential target protein for the compound's inhibitory effect, while it is interesting to highlight the possibility of interrupting CHIKV replication via interaction with host cellular factor. By complying the Lipinski's rule of five, hesperetin exhibits drug-like properties which projects its potential as a therapeutic option for CHIKV infection.
Tropical Infectious Disease Research and Education Centre, Department of Medical Microbiology Faculty of Medicine, University of Malaya , Kuala Lumpur , Malaysia.
Adrian
A
Oo
Tropical Infectious Disease Research and Education Centre, Department of Medical Microbiology Faculty of Medicine, University of Malaya , Kuala Lumpur , Malaysia.
Pouya
P
Hassandarvish
Department of Chemistry, University of Malaya , Kuala Lumpur , Malaysia.
Sek Peng
SP
Chin
Department of Chemistry, University of Malaya , Kuala Lumpur , Malaysia.
Vannajan Sanghiran
0000-0002-2911-7726
VS
Lee
Tropical Infectious Disease Research and Education Centre, Department of Medical Microbiology Faculty of Medicine, University of Malaya , Kuala Lumpur , Malaysia.
Sazaly
S
Abu Bakar
Tropical Infectious Disease Research and Education Centre, Department of Medical Microbiology Faculty of Medicine, University of Malaya , Kuala Lumpur , Malaysia.
Keivan
K
Zandi
Antiviral; Chikungunya virus; Computational approach; Hesperetin; In silico; Molecular docking; nsP3