Epigenetic proteins are highly sought-after targets in medicinal chemistry and drug discovery. In the recent years, considerable research efforts were focused on developing small molecules binding to bromodomains (BRD), the readers of acetyl-lysine modifications, due to their implication in numerous of diseases [1,2]. From the structural point of view of BRD, crystallographic studies describe, as a common feature, five water molecules as an integral part of the acetyl-lysine binding pocket, which are not only essential for its druggability but also as a functional part of the protein [3,4]. Following a fragment-based drug design, with the help of computational techniques, a series of fragments with 5-phenylthiazolo[2,3-c][1,2,4]triazole scaffold with a substituent at the 3-position were proposed, probing the hydrophobic properties of the water network site of BRD4(BD1) [5,6]. Using time-resolved fluorescence energy transfer (TR-FRET) assays and X-Ray crystallography, the most active fragment of this series SSR4 (IC50 26 µM) was characterised. In a following computational study with the help of NAOMInext software [7], optimized derivatives of SSR4 and a synthetic route were suggested, leading to a 650-fold potency jump. In this study we will describe the computational studies and chemical approaches applied to further improve the potency to obtain a lead candidate for BRD4 (BD1).

Design and synthesis of novel brd4-targeting molecules with computer-assisted fbdd

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.