Identification of potent BRD4‐BD1 inhibitors using classical and steered molecular dynamics based free energy analysis

Abstract

In the present work a combination of traditional and steered molecular dynamics based techniques were employed to identify potential inhibitors against the human BRD4 protein (BRD4‐ BD1); an established drug target for multiple illnesses including various malignancies. Quinoline derivatives that were synthesized in‐house were tested for their potential as new BRD4‐BD1 inhibitors. Initially molecular docking experiments were performed to determine the binding poses of BRD4‐BD1 inhibitors. To learn more about the thermodynamics of inhibitor binding to the BRD4‐BD1 active site, the Molecular Mechanics Poisson‐Boltzmann Surface Area (MM‐PBSA) free energy calculations were conducted afterwards. The findings of the MM‐PBSA analysis were further reinforced by performing steered umbrella sampling simulations which revealed crucial details about the binding/unbinding process of the most potent quinoline derivatives at the BRD4‐BD1 active site. We report a novel quinoline derivative which can be developed into a fully functional BRD4‐BD1 inhibitor after experimental validation. The identified compound (4 g) shows better properties than the standard BRD4‐BD1 inhibitors considered in the study. The study also highlights the crucial role of Gln78, Phe79, Trp81, Pro82, Phe83, Gln84, Gln85, Val87, Leu92, Leu94, Tyr97, Met105, Cys136, Asn140, Ile146 and Met149 in inhibitor binding. The study provides a possible lead candidate and key amino acids involved in inhibitor recognition and binding at the active site of BRD4‐BD1 protein. The findings might be of significance to medicinal chemists involved in the development of potent BRD4‐BD1 inhibitors.