Insilico Modelling and Comparative Docking Studies of EWS-FLI1 Responsible for Ewing Sarcoma in Human Beings

Abstract

Ewing’s sarcoma (EWS) is a small round-cell tumor typically arising in the bones, rarely in soft tissues, of children and adolescents. Patho-genomic translocations involving the EWS gene on chromosome 22 and an ETS-type gene (Fli1) on chromosome 11, are implicated in more than 95% of Ewing’s sarcomas. A chimeric transcript that consists of the N-terminus of EWS i.e., Transcriptional Activation Domain is fused to the C-terminal portion of FLI1 i.e., DNA Binding Domain (DBD). In this present study, the structure of disordered fusion protein, EWS-FLI1 was predicted, modelled and refined. Ligand structures were drawn by using CHEMDRAW and CORINA. Comparative Docking studies were performed for EWS-FLI1 protein with EMODIN and YK-4-279 by using SCHRODINGER. Although, EMODIN and YK-4-279 interacted with the protein by establishing the H-Bonds with SER 316, GLN 326, GLN 328, ASP 430 by the former and with SER 316, ALA 110, and GLN 109 with the later, a common residue of SER 316 was observed to be interacting. However, the docking score and Glide g score of -6.278203 and -6.100573 were observed for EMODIN and YK-4-279 respectively, which revealed EMODIN to be much more effective in presenting the highest value.  Molecular Dynamics Simulation was performed to analyse the stability of Docked structure of protein and ligand. For EMODIN, the stabilized structure was formed at 646 ps whereas for YK-4-279, the stabilized structure was formed at 680 ps and RMSD values for EMODIN was comparatively lower than YK-4-279.

Keywords: Ewing sarcoma, disordered fusion protein, natural ligand, comparison, molecular dynamic simulation