Probing the Histamine H Receptor Binding Site to Explore Ligand Binding Kinetics.

Analysis of structure-kinetic relationships (SKR) can contribute to an improved understanding of receptor-ligand interactions. Here, fragment (4-(2-benzylphenoxy)-1-methylpiperidine) was used in different fragment growing approaches to mimic the putative binding mode of the long residence time (RT) ligands olopatadine, acrivastine, and levocetirizine at the histamine H receptor (HR). SKR analyses reveal that introduction of a carboxylic acid moiety can increase RT at HR up to 11-fold.

The Role of Water Networks in Phosphodiesterase Inhibitor Dissociation and Kinetic Selectivity.

In search of new opportunities to develop Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) inhibitors that have selectivity over the off-target human PDE4 (hPDE4), different stages of a fragment-growing campaign were studied using a variety of biochemical, structural, thermodynamic, and kinetic binding assays. Remarkable differences in binding kinetics were identified and this kinetic selectivity was explored with computational methods, including molecular dynamics and interaction fingerprint analyses. These studies indicate that a key hydrogen bond between Gln and the inhibitors is exposed to a water channel in TbrPDEB1, leading to fast unbinding.

Pharmacological Characterization and Radiolabeling of VUF15485, a High-Affinity Small-Molecule Agonist for the Atypical Chemokine Receptor ACKR3.

Atypical chemokine receptor 3 (ACKR3), formerly referred to as CXCR7, is considered to be an interesting drug target. In this study, we report on the synthesis, pharmacological characterization and radiolabeling of VUF15485, a new ACKR3 small-molecule agonist, that will serve as an important new tool to study this -arrestin-biased chemokine receptor. VUF15485 binds with nanomolar affinity (pIC = 8.

Lead Optimization of the 5-Phenylpyrazolopyrimidinone NPD-2975 toward Compounds with Improved Antitrypanosomal Efficacy.

Human African trypanosomiasis (HAT) still faces few therapeutic options and emerging drug resistance, stressing an urgency for novel antitrypanosomal drug discovery. Here, we describe lead optimization efforts aiming at improving antitrypanosomal efficacy and better physicochemical properties based on our previously reported optimized hit NPD-2975 (pIC 7.2).

Fragment-to-Lead Medicinal Chemistry Publications in 2022.

This Perspective is the eighth in an annual series that summarizes successful fragment-to-lead (F2L) case studies published each year. A tabulated summary of relevant articles published in 2022 is provided, and features such as target class, screening methods, and ligand efficiency are discussed both for the 2022 examples and for the combined examples over the years 2015-2022. In addition, trends and new developments in the field are summarized.