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.

A high-affinity, cis-on photoswitchable beta blocker to optically control β-adrenergic receptors in vitro and in vivo.

This study introduces (S)-Opto-prop-2, a second-generation photoswitchable ligand designed for precise modulation of β-adrenoceptor (βAR). Synthesised by incorporating an azobenzene moiety with propranolol, (S)-Opto-prop-2 exhibited a high PSS (photostationary state for cis isomer) percentage (∼90 %) and a favourable half-life (>10 days), facilitating diverse bioassay measurements. In vitro, the cis-isomer displayed substantially higher βAR binding affinity than the trans-isomer (1000-fold), making (S)-Opto-prop-2 one of the best photoswitchable GPCR (G protein-coupled receptor) ligands reported so far.

Synthesis and Pharmacological Characterization of New Photocaged Agonists for Histamine H and H Receptors.

The modulation of biological processes with light-sensitive chemical probes promises precise temporal and spatial control. Yet, the design and synthesis of suitable probes is a challenge for medicinal chemists. This article introduces a photocaging strategy designed to modulate the pharmacology of histamine H receptors (HR) and H receptors (HR).

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.

PSW-Designer: An Open-Source Computational Platform for the Design and Virtual Screening of Photopharmacological Ligands.

Photoswitchable (PSW) molecules offer an attractive opportunity for the optical control of biological processes. However, the successful design of such compounds remains a challenging multioptimization endeavor, resulting in several biological target classes still relatively poorly explored by photoswitchable ligands, as is the case for G protein-coupled receptors (GPCRs). Here, we present the PSW-Designer, a fully open-source computational platform, implemented in the KNIME Analytics Platform, to design and virtually screen novel photoswitchable ligands for photopharmacological applications based on privileged scaffolds.

Multiplexed experimental strategies for fragment library screening against challenging drug targets using SPR biosensors.

Surface plasmon resonance (SPR) biosensor methods are ideally suited for fragment-based lead discovery.  However, generally applicable experimental procedures and detailed protocols are lacking, especially for structurally or physico-chemically challenging targets or when tool compounds are not available. Success depends on accounting for the features of both the target and the chemical library, purposely designing screening experiments for identification and validation of hits with desired specificity and mode-of-action, and availability of orthogonal methods capable of confirming fragment hits.

An Automated, Open-Source Workflow for the Generation of (3D) Fragment Libraries.

The recent success of fragment-based drug discovery (FBDD) is inextricably linked to adequate library design. To guide the design of our fragment libraries, we have constructed an automated workflow in the open-source KNIME software. The workflow considers chemical diversity and novelty of the fragments, and can also take into account the three-dimensional (3D) character.

Green Drug Discovery: Novel Fragment Space from the Biomass-Derived Molecule Dihydrolevoglucosenone (Cyrene).

Biomass-derived molecules can provide a basis for sustainable drug discovery. However, their full exploration is hampered by the dominance of millions of old-fashioned screening compounds in classical high-throughput screening (HTS) libraries frequently utilized. We propose a fragment-based drug discovery (FBDD) approach as an efficient method to navigate biomass-derived drug space.

SAR exploration of the non-imidazole histamine H receptor ligand ZEL-H16 reveals potent inverse agonism.

Histamine H receptor (H R) agonists without an imidazole moiety remain very scarce. Of these, ZEL-H16 (1) has been reported previously as a high-affinity non-imidazole H R (partial) agonist. Our structure-activity relationship analysis using derivatives of 1 identified both basic moieties as key interaction motifs and the distance of these from the central core as a determinant for H R affinity.

Optical control of the β-adrenergic receptor with opto-prop-2: A -active azobenzene analog of propranolol.

In this study, we synthesized and evaluated new photoswitchable ligands for the beta-adrenergic receptors β-AR and β-AR, applying an azologization strategy to the first-generation beta-blocker propranolol. The resulting compounds (Opto-prop-1, -2, -3) have good photochemical properties with high levels of light-induced - isomerization (>94%) and good thermal stability (  > 10 days) of the resulting -isomer in an aqueous buffer. Upon illumination with 360-nm light to PSS , large differences in binding affinities were observed for photoswitchable compounds at β-AR as well as β-AR.

Fragment Screening Yields a Small-Molecule Stabilizer of 14-3-3 Dimers That Modulates Client Protein Interactions.

The development of protein-protein interaction (PPI) inhibitors has been a successful strategy in drug development. However, the identification of PPI stabilizers has proven much more challenging. Here we report a fragment-based drug screening approach using the regulatory hub-protein 14-3-3 as a platform for identifying PPI stabilizers.

Escape from planarity in fragment-based drug discovery: A synthetic strategy analysis of synthetic 3D fragment libraries.

In fragment-based drug discovery (FBDD), there is a developing appreciation that 3D fragments could offer opportunities that are not provided by 2D fragments. This review provides an overview of the synthetic strategies that have been used to prepare 3D fragments, as discussed in 25 papers published from 2011 to mid-May 2020. Three distinct strategies are highlighted: (i) diversity-oriented synthesis; (ii) the synthesis and diversification of scaffolds; and (iii) computational design and synthesis (where 3D fragments were computationally enumerated and filtered on the basis of computationally generated 3D shape descriptors and other properties).

Puckering the Planar Landscape of Fragments: Design and Synthesis of a 3D Cyclobutane Fragment Library.

Fragment-based drug discovery (FBDD) has a growing need for unique screening libraries. The cyclobutane moiety was identified as an underrepresented yet attractive three-dimensional (3D) scaffold. Synthetic strategies were developed via a key 3-azido-cyclobutanone intermediate, giving potential access to a range of functional groups with accessible growth vectors.

Optical control of Class A G protein-coupled receptors with photoswitchable ligands.

The field of photopharmacology of Class A GPCR ligands has recently attracted attention. In this review we analyze 31 papers on currently available photoswitchable ligands for Class A GPCRs. Using the six most recurring terms of all combined paper abstracts, one can extract the overarching goal of this area of research: "Photoswitchable ligands control receptor activity with light" (represented in the TOC graphic).

Escape from planarity in fragment-based drug discovery: A physicochemical and 3D property analysis of synthetic 3D fragment libraries.

Fragment-based drug discovery (FBDD) has grown into a well-established approach in the pursuit of new therapeutics. Key to the success of FBDD is the low molecular complexity of the initial hits and this has resulted in fragment libraries that mainly contain compounds with a two-dimensional (2D) shape. In an effort to increase the chemical diversity and explore the impact of increased molecular complexity on the hit rate of fragment library screening, several academic and industrial groups have designed and synthesised novel fragments with a three-dimensional (3D) shape.

Exploring the Effect of Cyclization of Histamine H Receptor Antagonists on Ligand Binding Kinetics.

There is an increasing interest in guiding hit optimization by considering the target binding kinetics of ligands. However, compared to conventional structure-activity relationships, structure-kinetics relationships have not been as thoroughly explored, even for well-studied archetypical drug targets such as the histamine H receptor (HR), a member of the family A G-protein coupled receptor. In this study, we show that the binding kinetics of HR antagonists at the HR is dependent on the cyclicity of both the aromatic head group and the amine moiety of HR ligands, the chemotypes that are characteristic for the first-generation HR antagonists.

From recipe to research: introducing undergraduate students to the nature of science using a hybrid practical course centred on drug discovery for neglected diseases.

A hybrid undergraduate practical course involving synthetic medicinal chemistry on neglected diseases bridges the gap between skills, techniques and scientific research, and exposes students to the nature of science.

Bromo-Cyclobutenaminones as New Covalent UDP--Acetylglucosamine Enolpyruvyl Transferase (MurA) Inhibitors.

Drug discovery programs against the antibacterial target UDP--acetylglucosamine enolpyruvyl transferase (MurA) have already resulted in covalent inhibitors having small three- and five-membered heterocyclic rings. In the current study, the reactivity of four-membered rings was carefully modulated to obtain a novel family of covalent MurA inhibitors. Screening a small library of cyclobutenone derivatives led to the identification of bromo-cyclobutenaminones as new electrophilic warheads.

Covalent Inhibition of the Histamine H Receptor.

Covalent binding of G protein-coupled receptors by small molecules is a useful approach for better understanding of the structure and function of these proteins. We designed, synthesized and characterized a series of 6 potential covalent ligands for the histamine H receptor (HR). Starting from a 2-amino-pyrimidine scaffold, optimization of anchor moiety and warhead followed by fine-tuning of the required reactivity via scaffold hopping resulted in the isothiocyanate HR ligand .

A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light.

We report a detailed structure-activity relationship for the scaffold of VUF16216, a compound we have previously communicated as a small-molecule efficacy photoswitch for the peptidergic chemokine GPCR CXCR3. A series of photoswitchable azobenzene ligands was prepared through various synthetic strategies and multistep syntheses. Photochemical and pharmacological properties were used to guide the design iterations.

4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H Receptor Agonists with in Vivo Central Nervous System Activity.

Despite the high diversity of histamine H receptor (HR) antagonist/inverse agonist structures, partial or full HR agonists have typically been imidazole derivatives. An in-house screening campaign intriguingly afforded the non-imidazole 4-(3-azetidin-1-yl)pyrimidin-2-amine as a partial HR agonist. Here, the design, synthesis, and structure-activity relationships of analogues are described.

Modulators of CXCR4 and CXCR7/ACKR3 Function.

The two G protein-coupled receptors (GPCRs) C-X-C chemokine receptor type 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are part of the class A chemokine GPCR family and represent important drug targets for human immunodeficiency virus (HIV) infection, cancer, and inflammation diseases. CXCR4 is one of only three chemokine receptors with a US Food and Drug Administration approved therapeutic agent, the small-molecule modulator AMD3100. In this review, known modulators of the two receptors are discussed in detail.

Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors.

Several 3',5'-cyclic nucleotide phosphodiesterases (PDEs) have been validated as good drug targets for a large variety of diseases. Trypanosoma brucei PDEB1 (TbrPDEB1) has been designated as a promising drug target for the treatment of human African trypanosomiasis. Recently, the first class of selective nanomolar TbrPDEB1 inhibitors was obtained by targeting the parasite specific P-pocket.

Route to Prolonged Residence Time at the Histamine H Receptor: Growing from Desloratadine to Rupatadine.

Drug-target binding kinetics are an important predictor of in vivo drug efficacy, yet the relationship between ligand structures and their binding kinetics is often poorly understood. We show that both rupatadine () and desloratadine () have a long residence time at the histamine H receptor (HR). Through development of a [H]levocetirizine radiolabel, we find that the residence time of exceeds that of more than 10-fold.