In silico study on anti-Chikungunya virus activity of hesperetin

Abstract

BackgroundThe 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.Methods3D 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.ResultsWe 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.DiscussionThe 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.

In Silico Analysis of Compounds Isolated from Selected Indian Medicinal Plants against Chikungunya Viral Proteins

“…In a similar study, Hesperetin was screened for potential inhibitory activities against four CHIKV's nonstructural proteins, namely nsP1, nsP2, nsP3 and nsP4 in addition to SPK2 via the docking of the compound to each protein. Hesperetin exhibited the strongest binding affinity against 3GPG (-8.5 kcal/mol), followed by nsP4 and SPK2 (-7.7 kcal/mol), nsP1 (-7.6 kcal/ mol) and finally 3TRK (-6.9 kcal/mol) [19] . Similarly, Suramin, an antiparasitic drug, several chemical compounds had been tested for its anti-CHIK activity by docking [20,21] .…”

Flavonoids: promising natural compounds against viral infections

“…In the same study, hesperetin, another flavanone which is found richly in citrus fruits, was found to exert most potent anti-CHIKV effect during the virus intracellular replication, with an IC 50 of 8.5 lM [1]. Molecular docking and molecular dynamics studies by Oo et al also revealed strong and stable interactions between hesperetin and CHIKV nonstructural protein 2 (nsP2) as well as non-structural protein 3 (nsP3), suggesting that these proteins may be the target of hesperetin's anti-CHIKV activity [101].…”

In silico study of chikungunya polymerase, a potential target for inhibitors

“…nsP1, nsP2, nsP3, nsP4 and five structural proteins i.e. capsid (C), envelope glycoprotein E1, E2, E3 and 6k [7,11,17,21]. nsPs play a key role in the intracellular replication of CHIKV [17].…”

“…capsid (C), envelope glycoprotein E1, E2, E3 and 6k [7,11,17,21]. nsPs play a key role in the intracellular replication of CHIKV [17]. Inside the host cell, nascent single polypeptide P1234 is formed which is then cleaved to mature nsP4 and precursor P123 replication complex, which is further processed to produce nsp1 and P23 complex and finally the cleavage of P23 results in mature nsP1, nsP2, nsP3, nsP4 [11,22,25].…”

“…Several molecules having the inhibitory effect on CHIKV replication have been reported but few studies were documented on nsP4 as a target. Benzimidazole-related compound [26], ribavirin, diketo acid derivative [15], hesperetina flavanoid derivatives [17], compound A [2] and favipiravir [9] are some compounds already reported in the literature exhibiting anti-CHIKV nsP4 activity. But all of these molecules are still at the experimental level as far as their use in CHIKV intervention is concerned.…”