Introducing structure-based three-dimensional pharmacophore models for accelerating the discovery of selective BRD9 binders

Repositioning of Quinazolinedione-Based Compounds on Soluble Epoxide Hydrolase (sEH) through 3D Structure-Based Pharmacophore Model-Driven Investigation

“…As above reported, we recently developed a 3D structure-based pharmacophoric model for sEH, since it represents a target of our interest (see Section 1), in order to facilitate the identification of possible anti-inflammatory and anticancer agents. It is important to note that the use of this specific computational tool led us to the successful identification of novel bromodomain-containing protein-9 (BRD9) inhibitors after developing pharmacophore models specifically built for this protein module [4]. In details, we here implemented a 3D structure-based pharmacophore model directly built in the binding site of sEH (X-ray protein structure with PDB code: 5AI5 [40]).…”

“…Indeed, in silico methods represent excellent tools for the repositioning of different molecular platforms, including already approved drugs, natural products with unknown mechanisms, and newly synthesized compounds designed for a given target but not performing as expected. In this work, we show the successful repositioning of a small set of compounds employing a 3D structure-based pharmacophore model-driven approach [4], which finally led to new inhibitors of soluble epoxide hydrolase (sEH). sEH, belonging to the arachidonic acid cascade and involved in inflammatory pathologies, represents an interesting target deeply investigated in the last years for the treatment of inflammation and related disorders.…”

“…(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(6-iodopyridin-3-yl)hexanamide was obtained by following the general procedure (A-B) as a brown solid (240 mg, 20% yield after HPLC purification). RP-HPLC t R = 22.7 min, gradient condition: from 5% B ending to 100% B 50 min, flow rate of 4 mL/min, λ = 240 nm 1.…”

6‐Methylquinazolin‐4(3H)‐one Based Compounds as BRD9 Epigenetic Reader Binders: A Rational Combination of in silico Studies and Chemical Synthesis

“…In this way, we firstly assessed whether the chosen core would feature minimum requirements to bind BRD9 (according to "pharmfragment" model) and, secondly, the possible functionalization positions were identified on the selected poses in order to rationally design optimized derivatives (according to "pharm-druglike1" and "pharm-druglike2" models). [6] The obtained results highlighted three possible binding modes, here named "binding mode 1", "binding mode 2", and "binding mode 3" (Figure 1A, Figure 1C and Figure S2C), in which three different portions of the chemical core covered the acetyl lysine mimic function specifically represented by the two of the four features of "pharm-fragment" model, namely "A" as H-bond acceptor group and "H" as a hydrophobic feature. Subsequently, the three selected poses of the 6-methylquinazolin-4(3H)-one scaffold were analyzed according to the "pharm-druglike2" and "pharm-druglike1" pharmacophore models (Figure 1 and Figure S2) to evaluate which of the models could be accounted for the subsequent design of optimized derivatives.…”

“…Subsequently, the output docking poses were screened through 3D structure‐based pharmacophore model, i. e., AHRR 4‐points model (“pharm‐fragment”), AAHHRRR 7‐points model (“pharm‐druglike1”) and AAHRRRX 7 points model (“pharm‐druglike2”) developed by us and previously reported (Figure 1 and Figure S1). In this way, we firstly assessed whether the chosen core would feature minimum requirements to bind BRD9 (according to “pharm‐fragment” model) and, secondly, the possible functionalization positions were identified on the selected poses in order to rationally design optimized derivatives (according to “pharm‐druglike1” and “pharm‐druglike2” models) [6] . The obtained results highlighted three possible binding modes, here named “binding mode 1”, “binding mode 2”, and “binding mode 3” (Figure 1A, Figure 1C and Figure S2C), in which three different portions of the chemical core covered the acetyl lysine mimic function specifically represented by the two of the four features of “pharm‐fragment” model, namely “A” as H‐bond acceptor group and “H” as a hydrophobic feature.…”