IDENTIFICATION OF POTENT BROMODOMAIN4 (BRD4) INHIBITORS BY ENERGY-PHARMACOPHORE BASED VIRTUAL SCREENING TO TARGET BRD4-NUT MIDLINE CARCINOMA
Journal Title: International Journal of Pharmacy and Pharmaceutical Sciences - Year 2015, Vol 7, Issue 4
Abstract
Objective: Protein-protein interactions (PPI’s) have been used as a target in various diseases. One such major role of PPI’s comes when the protein Bromodomain4 (BRD4) reads the epigenetic changes in the histones and regulates transcription. This protein has been shown by various research groups to be linked to a rare form of cancer called BRD4-NUT midline carcinoma. The present study incorporates understanding the role of BRD4 in such cancer and as is directed towards finding new lead compounds to target the PPI involved.Methods: To find potential lead molecules against BRD4 protein, contact based and e-pharmacophore based virtual screening studies approach was adopted with the use of PHASE and E-pharmacophore module of the Schrödinger Maestro tool. Based on the pharmacophore hypothesis developed, virtual screening was performed for 22, 70, 000 Clean Lead-like compounds from the ZINC database by Virtual Screening Workflow of Schrödinger Maestro. Further Molecular dynamics simulations by GROMACS 4.5.5 were performed to study the energetics and stability of the top most docked ligands with BRD4 protein.Results: Pharmacophore based virtual screening studies results in the retrieval of three potential lead molecules, ZINC68155904, ZINC67910065, and ZINC6710456 from ZINC database which interacts with BRD4 protein with Glide score of-9.98,-8.31,-7.61 kJ/mol respectively. The desired interaction of this ligands with Asn140, Pro82 and Tyr 97 of BRD4 protein showed that the final hits have the potency of forming a stable complex. Molecular dynamics simulations studies also support the stability of the BRD4-ligand docked complex.Conclusion: The above study shows three compounds obtained viz ZINC68155904, ZINC67910065, and ZINC6710456 may serve as potential lead compounds which can act against BRD4 protein.Â
Authors and Affiliations
Sapam Tuleshwori Devi, Himani Tandon, Dinakara Rao Ampasala
Keywords
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