Potential entry inhibitors of the envelope protein (E2) of Chikungunya virus: in silico structural modeling, docking and molecular dynamic studies

Abstract

Chikungunya fever is an arboviral infection caused by the Chikungunya virus (CHIKV) and is transmitted by Aedes mosquito. The envelope protein (E2) of Chikungunya virus is involved in attachment of virion with the host cell. The present study was conceptualized to determine the structure of E2 protein of CHIKV and to identify the potential viral entry inhibitors. The secondary and tertiary structure of E2 protein was determined using bioinformatics tools. The mutational analysis of the E2 protein suggested that mutations may stabilize or de-stabilize the structure which may affect the structure-function relationship. In silico screening of various compounds from different databases identified two lead molecules i.e. phenothiazine and bafilomycin. Molecular docking and MD simulation studies of the E2 protein and compound complexes was carried out. This analysis revealed that bafilomycin has high docking score and thus high binding affinity with E2 protein suggesting stable protein-ligand interaction. Further, MD simulations suggested that both the compounds were stabilizing E2 protein. Thus, bafilomycin and phenothiazine may be considered as the lead compounds in terms of potential entry inhibitor for CHIKV. Further, these results should be confirmed by comprehensive cell culture, cytotoxic assays and animal experiments. Certain derivatives of phenothiazines can also be explored in future studies for entry inhibitors against CHIKV. The present investigation thus provides insight into protein structural dynamics of the envelope protein of CHIKV. In addition the study also provides information on the dynamics of interaction of E2 protein with entry inhibitors that will contribute towards structure based drug design.

Global transmission and evolutionary dynamics of the Chikungunya virus

“…Here ‘interacting alleles’ are referred to the alleles shortlisted for having maximum interaction scores with the peptides in E1 protein using the results of IEDB server analysis. Docking was done using the methodology previously described [29]…”

Computer-Aided Design, Synthesis, and Antiviral Evaluation of Novel Acrylamides as Potential Inhibitors of E3-E2-E1 Glycoproteins Complex from Chikungunya Virus

“…Still, it hydrophobically interacts with Leu 42 , Val 179 , Tyr 180 , Asn 264 , Pro 265 , and Val 266 , while also interacting with Ser 120 and Tyr 122 amino acids, via hydrogen bonding interactions at distances of 2.07 and 2.1 Å, respectively ( Figure 9 C). Additionally, in silico studies involving E3-E2-E1 glycoproteins have been developed focusing on virtual screening of phenothiazines, bafilomycin [ 85 ], and FAD-approved antimicrobial agents, such as cefmenoxime, ceforanide, cefotetan, cefonicid sodium, and cefpiramide [ 86 ]. Recently, Song et al (2019) [ 87 ] reported the crystal structures of the free mouse MXRA8 (mMXR8) receptor and the complex between human MXRA8 (hMXRA8) and the CHIKV E3-E2-E1 glycoproteins complex.…”

Virtual screening of inhibitors against Envelope glycoprotein of Chikungunya Virus: a drug repositioning approach

“…Arg36 and Ile37 in E2 protein, and Thr53, Tyr233, Gln235 and Ser238 in E1 protein are conserved in all Indian CHIKV strains and play an essential role in the formation of E1-E2 heterodimer 27, 10. These residues form hydrogen as well as hydrophobic bond with almost all the ligands adding significance to our docking results as leads interacting with these residues will have better chances of interfering with E1-E2 conformational changes during entry of CHIKV in the host cell and are worthy of further examination.…”