Exploration of Potential Ewing Sarcoma Drugs from FDA-Approved Pharmaceuticals through Computational Drug Repositioning, Pharmacogenomics, Molecular Docking, and MD Simulation Studies

Abstract

Novel drug development is a time-consuming process with relatively high debilitating costs. To overcome this problem, computational drug repositioning approaches are being used to predict the possible therapeutic scaffolds against different diseases. In the current study, computational drug repositioning approaches were employed to fetch the promising drugs from the pool of FDA-approved drugs against Ewing sarcoma. The binding interaction patterns and conformational behaviors of screened drugs within the active region of Ewing sarcoma protein (EWS) were confirmed through molecular docking profiles. Furthermore, pharmacogenomics analysis was employed to check the possible associations of selected drugs with Ewing sarcoma genes. Moreover, the stability behavior of selected docked complexes (drugs-EWS) was checked by molecular dynamics simulations. Taken together, astemizole, sulfinpyrazone, and pranlukast exhibited a result comparable to pazopanib and can be used as a possible therapeutic agent in the treatment of Ewing sarcoma.

Exploration of Flavonoids as Lead Compounds against Ewing Sarcoma through Molecular Docking, Pharmacogenomics Analysis, and Molecular Dynamics Simulations

“…In addition to its shape and location inside a protein, a binding pocket’s function is determined by the collection of amino acid residues that surround it [ 21 ]. The binding pocket residues of EWS were retrieved from an already published research article [ 13 ] and selected as Ser361, Met397, Ala362, His399, Tyr401, Thr414, and Ser416 ( Figure 3 ).…”

“…The position of a ligand in the protein’s holo-structure most likely determines the binding pocket of targeted protein and channels [ 21 ]. The active binding site residues were selected from previously published data [ 13 ] and identified using Discovery Studio and UCSF Chimera 1.10.1.…”

“…The CDOCKER module of Discovery Studio was employed to perform molecular docking of flavonoids to EWS. The attribute of the binding pocket sphere was modified as (X = 8.6488, Y = 3.7819 and Z = 2.6209) and the radius value was adjusted to 6.6378 [ 13 ] for a better conformational position in the active region of the target protein. The ligands (flavonoids) were docked individually to EWS with the default orientation and conformation 10/10.…”

“…Moreover, the C-terminus of EWS-FLI1 maintains FLI1’s DNA-binding domain and specifically interacts with the ACCGGAAG central sequence. EWS-FLI1 primarily binds to GGAA-repetitive areas, resulting in an association between GGAA microsatellites, EWS-FLI1 binding, and target gene expression [ 13 ].…”

Vismodegib Identified as a Novel COX-2 Inhibitor via Deep-Learning-Based Drug Repositioning and Molecular Docking Analysis

“…The position of a ligand in the protein's holo-structure most likely determines the binding pocket of the protein. 39 The complex of COX-2 and inhibitor, Vioxx, was retrieved from PDB (PDB ID: 5KIR). The interacting amino acids were selected using the ligand interaction approach of Discovery Studio for the accuracy of binding site generation.…”