Utkarsh Raj, Himansu Kumar, Saurabh Gupta and Pritish Kumar Varadwaj Pages 313 - 321 ( 9 )
Background: The modulation of the chromatin structure and repression of the transcription process has been done by Polycomb Repressive Complex 2 (PRC2) due to trimethylation of LYS27 of histone H3 (H3K27me3). This process is necessary for protein protein interaction (PPI) between EZH2 and EED catalytic subunits. The dysregulation of this complex is responsible for tumorigenesis and progression, making it an important cancer epigenetic therapeutic target. However, until now, there is only one FDA-approved drug called Astemizole has been reported to disrupt interactions between EZH2-EED.Objective: Identification of novel inhibitors for disrupting EZH2-EED interactions through virtual screening, docking and simulation. Methodology: In this study, we identified five compounds from in-silico screening & docking studies of a database of ~70000 compounds, which show better binding affinities than Astemizole. These compounds cause destabilization of PRC2 complex by disrupting the interaction between EZH2- EED and which in turn, inhibits its methyltransferase activity in cancerous cells. Molecular Dynamics (MD) Simulation analysis of the best receptor-ligand complex for 50 ns has exhibited that the top-scoring compound captures the expansion of PRC2-driven lymphomas primarily by deregulating PRC2 complex. Further, ADMET properties were analyzed to check their drug like properties. Results/Conclusion: Our study demonstrates not just the importance of in-silico drug discovery merely but also provides a range of small molecules that can hold the potential to serve as probable lead candidates for disrupting interactions between EZH2-EED. Hence, it has been suggested that the top screened compound C1 can prove to be more potent to inhibit PRC2-driven human cancers.
Docking, EED, EZH2, molecular dynamics, PPI, PRC2.
Department of Bioinformatics, Indian Institute of Information Technology-Allahabad, UP, India.