Identification and characterization of potent inhibitors by exploring the interaction interfaces between Envelope protein of SARS-CoV-2 and host protein –H2A and BRD2/4 (Dr.Shailendra Asthana)
Based on the protein-protein interactions (PPIs) map and other studies, it is known that the viral Envelope (E) protein interacts with human proteins and its role in developing the SARS-CoV-2 infection . There is evidence that BRD2, a bromodomain protein that specifically binds to acetylated chromatin to regulate the gene transcription, interacts with SARS-CoV-2 envelope proteins. The viral E protein acts as a kind of molecular mimic, damaging the interaction between histone (H2A) and BRD2 to disrupt BRD2 controlled transcription programs in a way beneficial to the virus. Based on available wealth of co-crystals and known inhibitors (ABBV-744, CPI-0610, 6BE6, MZ1, JQ1 and RVX-208) both the ligand- and structure-based approaches will be applicable to identify the chemical compounds. The ligand-based virtual screening will evaluate a 2D fingerprint, pharmacophore and 3D similarity to mimic the known compounds with different chemical scaffolds. The chemical libraries will be screened and ranked based on the best docking scores as well as binding energies as per the guidelines. The top 25% (max. 100) or top 100 hits to be selected from docking exercise and the best 10 to be used for molecular dynamics simulations for more qualitative and quantitative analysis, and based on binding free energy, thermodynamic profiling and potent interaction map the compounds will be selected for experimental evaluation.