Stereochemical optimization of ,2-substituted cycloalkylamines as norepinephrine reuptake inhibitors.

The norepinephrine transporter (NET), encoded by the SLC6A2 gene, is one of three key monoamine neurotransmitter transporters. Inhibition of NET-mediated reuptake of norepinephrine by monoamine reuptake inhibitors has been the main therapeutic strategy to treat disorders such as depression, ADHD and Parkinson's disease. Nevertheless, lack of efficacy as well as risk of adverse effects are still common for these treatments underscoring the necessity to improve drug discovery efforts for this target.

Labeling of CC Chemokine Receptor 2 with a Versatile Intracellular Allosteric Probe.

Interest in affinity-based probes (AfBPs) as novel tools to interrogate G protein-coupled receptors (GPCRs) has gained traction in recent years. AfBPs represent an interesting and more versatile alternative to antibodies. In the present study, we report the development and validation of AfBPs that target the intracellular allosteric pocket of CCR2, a GPCR of interest for the development of therapies targeting autoimmune and inflammatory diseases and also cancer.

CC chemokine receptor 2 is allosterically modulated by sodium ions and amiloride derivatives through a distinct sodium ion binding site.

CC chemokine receptor 2 and CCL2 are highly involved in cancer growth and metastasis, and immune escape. Raised sodium ion concentrations in solid tumours have also been correlated to metastasis and immune modulation. Sodium ions can modulate class A G protein-coupled receptors through the sodium ion binding site characterized by a highly conserved aspartic acid residue (D), also present in CCR2.

Advancing drug discovery through assay development: a survey of tool compounds within the human solute carrier superfamily.

With over 450 genes, solute carriers (SLCs) constitute the largest transporter superfamily responsible for the uptake and efflux of nutrients, metabolites, and xenobiotics in human cells. SLCs are associated with a wide variety of human diseases, including cancer, diabetes, and metabolic and neurological disorders. They represent an important therapeutic target class that remains only partly exploited as therapeutics that target SLCs are scarce.

-Acyl--Alkyl Sulfonamide Probes for Ligand-Directed Covalent Labeling of GPCRs: The Adenosine A Receptor as Case Study.

Small molecular tool compounds play an essential role in the study of G protein-coupled receptors (GPCRs). However, tool compounds most often occupy the orthosteric binding site, hampering the study of GPCRs upon ligand binding. To overcome this problem, ligand-directed labeling techniques have been developed that leave a reporter group covalently bound to the GPCR, while allowing subsequent orthosteric ligands to bind.

Exploring novel dilazep derivatives as hENT1 inhibitors and potentially covalent molecular tools.

The human equilibrative nucleoside transporter 1 (SLC29A1, hENT1) is a solute carrier that modulates the passive transport of nucleosides and nucleobases, such as adenosine. This nucleoside regulates various physiological processes, such as vasodilation and -constriction, neurotransmission and immune defense. Marketed drugs such as dilazep and dipyridamole have proven useful in cardiovascular afflictions, but the application of hENT1 inhibitors can be beneficial in a number of other diseases.

Label-free detection of prostaglandin transporter (SLCO2A1) function and inhibition: insights by wound healing and TRACT assays.

The prostaglandin transporter (PGT, SLCO2A1) mediates transport of prostanoids (a.o. prostaglandin E2 (PGE)) into cells and thereby promotes their degradation.

Pharmacological characterization of allosteric modulators: A case for chemokine receptors.

Chemokine receptors are relevant targets for a multitude of immunological diseases, but drug attrition for these receptors is remarkably high. While many drug discovery programs have been pursued, most prospective drugs failed in the follow-up studies due to clinical inefficacy, and hence there is a clear need for alternative approaches. Allosteric modulators of receptor function represent an excellent opportunity for novel drugs, as they modulate receptor activation in a controlled manner and display increased selectivity, and their pharmacological profile can be insurmountable.

Computational Characterization of Membrane Proteins as Anticancer Targets: Current Challenges and Opportunities.

Cancer remains a leading cause of mortality worldwide and calls for novel therapeutic targets. Membrane proteins are key players in various cancer types but present unique challenges compared to soluble proteins. The advent of computational drug discovery tools offers a promising approach to address these challenges, allowing for the prioritization of "wet-lab" experiments.

The Concise Guide to PHARMACOLOGY 2023/24: Ion channels.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.

Small-molecule CEM3 strengthens single-cell oscillators in the suprachiasmatic nucleus.

A robust endogenous clock is required for proper function of many physiological processes. The suprachiasmatic nucleus (SCN) constitutes our central circadian clock and allows us to adapt to daily changes in the environment. Aging can cause a decline in the amplitude of circadian rhythms in SCN and peripheral clocks, which contributes to increased risk of several chronic diseases.

Molecular insights into disease-associated glutamate transporter (EAAT1 / ) variants using and approaches.

Glutamate is an essential excitatory neurotransmitter and an intermediate for energy metabolism. Depending on the tumor site, cancer cells have increased or decreased expression of excitatory amino acid transporter 1 or 2 (EAAT1/2, ) to regulate glutamate uptake for the benefit of tumor growth. Thus, EAAT1/2 may be an attractive target for therapeutic intervention in oncology.

The translational value of ligand-receptor binding kinetics in drug discovery.

The translation of in vitro potency of a candidate drug, as determined by traditional pharmacology metrics (such as EC/IC and K/K values), to in vivo efficacy and safety is challenging. Residence time, which represents the duration of drug-target interaction, can be part of a more comprehensive understanding of the dynamic nature of drug-target interactions in vivo, thereby enabling better prediction of drug efficacy and safety. As a consequence, a prolonged residence time may help in achieving sustained pharmacological activity, while transient interactions with shorter residence times may be favourable for targets associated with side effects.

3DDPDs: describing protein dynamics for proteochemometric bioactivity prediction. A case for (mutant) G protein-coupled receptors.

Proteochemometric (PCM) modelling is a powerful computational drug discovery tool used in bioactivity prediction of potential drug candidates relying on both chemical and protein information. In PCM features are computed to describe small molecules and proteins, which directly impact the quality of the predictive models. State-of-the-art protein descriptors, however, are calculated from the protein sequence and neglect the dynamic nature of proteins.

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The adenosine A receptor (AAR) is a G protein-coupled receptor (GPCR) that exerts immunomodulatory effects in pathophysiological conditions such as inflammation and cancer. Thus far, studies toward the downstream effects of AAR activation have yielded contradictory results, thereby motivating the need for further investigations. Various chemical and biological tools have been developed for this purpose, ranging from fluorescent ligands to antibodies.

Kinetic profiling of novel spirobenzo-oxazinepiperidinone derivatives as equilibrative nucleoside transporter 1 inhibitors.

Evaluation of kinetic parameters of drug-target binding, k, k, and residence time (RT), in addition to the traditional in vitro parameter of affinity is receiving increasing attention in the early stages of drug discovery. Target binding kinetics emerges as a meaningful concept for the evaluation of a ligand's duration of action and more generally drug efficacy and safety. We report the biological evaluation of a novel series of spirobenzo-oxazinepiperidinone derivatives as inhibitors of the human equilibrative nucleoside transporter 1 (hENT1, SLC29A1).

Proteochemometric Modeling Identifies Chemically Diverse Norepinephrine Transporter Inhibitors.

Solute carriers (SLCs) are relatively underexplored compared to other prominent protein families such as kinases and G protein-coupled receptors. However, proteins from the SLC family play an essential role in various diseases. One such SLC is the high-affinity norepinephrine transporter (NET/SLC6A2).

DrugEx v3: scaffold-constrained drug design with graph transformer-based reinforcement learning.

Rational drug design often starts from specific scaffolds to which side chains/substituents are added or modified due to the large drug-like chemical space available to search for novel drug-like molecules. With the rapid growth of deep learning in drug discovery, a variety of effective approaches have been developed for de novo drug design. In previous work we proposed a method named DrugEx, which can be applied in polypharmacology based on multi-objective deep reinforcement learning.

Papyrus: a large-scale curated dataset aimed at bioactivity predictions.

With the ongoing rapid growth of publicly available ligand-protein bioactivity data, there is a trove of valuable data that can be used to train a plethora of machine-learning algorithms. However, not all data is equal in terms of size and quality and a significant portion of researchers' time is needed to adapt the data to their needs. On top of that, finding the right data for a research question can often be a challenge on its own.

Impact of cancer-associated mutations in CC chemokine receptor 2 on receptor function and antagonism.

CC chemokine receptor 2 (CCR2), a G protein-coupled receptor, plays a role in many cancer-related processes such as metastasis formation and immunosuppression. Since ∼ 20 % of human cancers contain mutations in G protein-coupled receptors, ten cancer-associated CCR2 mutants obtained from the Genome Data Commons were investigated for their effect on receptor functionality and antagonist binding. Mutations were selected based on either their vicinity to CCR2's orthosteric or allosteric binding sites or their presence in conserved amino acid motifs.

Pan-cancer functional analysis of somatic mutations in G protein-coupled receptors.

G Protein-coupled receptors (GPCRs) are the most frequently exploited drug target family, moreover they are often found mutated in cancer. Here we used a dataset of mutations found in patient samples derived from the Genomic Data Commons and compared it to the natural human variance as exemplified by data from the 1000 genomes project. We explored cancer-related mutation patterns in all GPCR classes combined and individually.

A Chemical Biological Approach to Study G Protein-Coupled Receptors: Labeling the Adenosine A Receptor Using an Electrophilic Covalent Probe.

G protein-coupled receptors (GPCRs) have been known for decades as attractive drug targets. This has led to the development and approval of many ligands targeting GPCRs. Although ligand binding effects have been studied thoroughly for many GPCRs, there are multiple aspects of GPCR signaling that remain poorly understood.

Development of subtype-selective covalent ligands for the adenosine A receptor by tuning the reactive group.

Signalling through the adenosine receptors (ARs), in particular through the adenosine A receptor (AAR), has been shown to play a role in a variety of pathological conditions, ranging from immune disorders to cancer. Covalent ligands for the AAR have the potential to irreversibly block the receptor, as well as inhibit all AAR-induced signalling pathways. This will allow a thorough investigation of the pathophysiological role of the receptor.