Identification of structural motifs in the E2 glycoprotein of Chikungunya involved in virus - host interaction
J. Asnet Mary, R. Paramasivan, B.K. Tyagi, Surender Mohan and R. Shenbagarathai [1]
Molecular Tour
Chikungunya fever is one of the reemerging vector-borne diseases. It has become a major global health problem especially in the developing countries. There are no vaccines or specific antiviral drugs available till date. Understanding the structural aspects of E2 glycoprotein is crucial to develop specific inhibitors to prevent the virus binding from host receptors. This study reports small molecule inhibitors of envelope glycoprotein 2 (E2 glycoprotein) which are predicted based on Chikungunya virus–host interactions. E2 glycoprotein of Chikungunya virus interacts at 216 residue of the host receptor protein which plays a vital role in initiating infection. In silico method was adopted to predict the sequence motifs of envelope protein, as the method like yeast two hybrid system is laborious, time consuming, and costly. The of the Indian isolate was modeled using two templates (2XFC and 3JOC) and then validated as none of the structures include carboxy terminal domain of E2. Generally, protein-protein interactions are mediated by a short stretch of peptides of 3–10 aa called linear motifs that captures the key features of binding. The E2 glycoprotein was shown to contain sequence motifs such as at 213–216 amino acids. These sites are reported as binding site for host receptor protein, heparan sulfate (HS) in a RRV mutant as well as the Fab binding site for SINV- and RRV-neutralizing antibodies in previous reports. PDZ domains have a single binding site containing carboxylate binding loop (R/KXXX-G-Φ-G-Φ motif, where X is any amino acid residue and Φ is hydrophobic residues), which is highly conserved. The corresponding peptide structures which recognize the PDZ domain binding motif were identified by the literature search. The peptides such as (colored in darkmagenta), (colored in magenta), (colored in coral), and TFGF were docked by induced fit docking protocol. These peptides were used for generating five point pharmacophore model (ADDDR) containing acceptor, donor and aromatic ring features. Databases such as Asinex, TosLab and Maybridge were searched for the matches for the predicted pharmacophore model. Two compounds were identified as lead molecules as their glide score is >5 kcal/mol. These two compounds could be used as leads for designing new compounds by adding the interactive groups which may increase the interaction. Since the pharmacophore model is developed based on Chikungunya virus–host interaction, it can be used for designing promising antiviral lead compounds for the treatment of Chikungunya fever.
