Automated design of multi-target ligands by generative deep learning.

Generative deep learning models enable data-driven de novo design of molecules with tailored features. Chemical language models (CLM) trained on string representations of molecules such as SMILES have been successfully employed to design new chemical entities with experimentally confirmed activity on intended targets. Here, we probe the application of CLM to generate multi-target ligands for designed polypharmacology.

A High-Quality Photoswitchable Probe that Selectively and Potently Regulates the Transcription Factor RORγ.

Retinoic acid receptor-related orphan receptor γ (RORγ) is a nuclear hormone receptor with multiple biological functions in circadian clock regulation, inflammation, and immunity. Its cyclic temporal role in circadian rhythms, and cell-specific activity in the immune system, make it an intriguing target for spatially and temporally localised pharmacology. To create tools that can study RORγ biology with appropriate spatiotemporal resolution, we designed light-dependent inverse RORγ agonists by building azobenzene photoswitches into ligand consensus structures.

Development of Tailless Homologue Receptor (TLX) Agonist Chemical Tools.

The human tailless homologue receptor (TLX) is a ligand-activated transcription factor acting as a master regulator of neural stem cell homeostasis. Despite its promising potential in neurodegenerative disease treatment, TLX ligands are rare but required to explore phenotypic effects of TLX modulation and for target validation. We have systematically studied and optimized a TLX agonist scaffold obtained by fragment fusion.

Development of Nurr1 agonists from amodiaquine by scaffold hopping and fragment growing.

The neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) has shown great promise as a therapeutic target in Parkinson's and Alzheimer's disease as well as multiple sclerosis but high-quality chemical tools for pharmacological target validation of Nurr1 are rare. We have employed the weak Nurr1 modulator amodiaquine (AQ) and AQ-derived fragments as templates to design a new Nurr1 agonist chemotype by scaffold hopping and fragment growing strategies. Systematic structural optimization of this scaffold yielded Nurr1 agonists with nanomolar potency and binding affinity.

Chemogenomics for NR1 nuclear hormone receptors.

Nuclear receptors (NRs) regulate transcription in response to ligand binding and NR modulation allows pharmacological control of gene expression. Although some NRs are relevant as drug targets, the NR1 family, which comprises 19 NRs binding to hormones, vitamins, and lipid metabolites, has only been partially explored from a translational perspective. To enable systematic target identification and validation for this protein family in phenotypic settings, we present an NR1 chemogenomic (CG) compound set optimized for complementary activity/selectivity profiles and chemical diversity.

Structure-Guided Design of a Highly Potent Partial RXR Agonist with Superior Physicochemical Properties.

Retinoid X receptors (RXRs, NR2B1-3) hold therapeutic potential in oncology, neurodegeneration, and metabolic diseases, but traditional RXR agonists mimicking the natural ligand 9- retinoic acid exhibit poor physicochemical properties, pharmacokinetics, and safety profiles. Improved RXR ligands are needed to exploit RXR modulation as a promising therapeutic concept in various indications beyond its current role in second-line cancer treatment. Here, we report the co-crystal structure of RXR in complex with a novel pyrimidine-based ligand and the structure-informed optimization of this scaffold to highly potent and highly soluble RXR agonists.

No NLRP3 inflammasome activity in kidney epithelial cells, not even when the NLRP3-A350V Muckle-Wells variant is expressed in podocytes of diabetic mice.

Background: The NLRP3 inflammasome integrates several danger signals into the activation of innate immunity and inflammation by secreting IL-1β and IL-18. Most published data relate to the NLRP3 inflammasome in immune cells, but some reports claim similar roles in parenchymal, namely epithelial, cells. For example, podocytes, epithelial cells critical for the maintenance of kidney filtration, have been reported to express NLRP3 and to release IL-β in diabetic kidney disease, contributing to filtration barrier dysfunction and kidney injury.

Structural Modification of the Natural Product Valerenic Acid Tunes RXR Homodimer Agonism.

Retinoid X receptors (RXR) are ligand-sensing transcription factors with a unique role in nuclear receptor signaling as universal heterodimer partners. RXR modulation holds potential in cancer, neurodegeneration and metabolic diseases but adverse effects of RXR activation and lack of selective modulators prevent further exploration as therapeutic target. The natural product valerenic acid has been discovered as RXR agonist with unprecedented preference for RXR subtype and homodimer activation.

A "Kidney-on-the-Chip" Model Composed of Primary Human Tubular, Endothelial, and White Blood Cells.

State-of-the-art cell culture systems may enlist a variety of features to push the significance of in vitro models beyond classical 2D single cell culture; among them are the 3D scaffolds of organic or artificial materials, multi-cell setups, and the use of primary cells as source materials. Obviously, operational complexity increases with each additional feature and feasibility, whereas reproducibility may suffer.We report a multicellular setup using primary human cells and the Mimetas scaffold that aims to increase pathophysiological significance of in vitro culture and simultaneously allows for relatively high-throughput and easy handling.

Targeting the Alternative Vitamin E Metabolite Binding Site Enables Noncanonical PPARγ Modulation.

The lipid-sensing transcription factor PPARγ is the target of antidiabetic thiazolidinediones (TZD). At two sites within its ligand binding domain, it also binds oxidized vitamin E metabolites and the vitamin E mimetic garcinoic acid. While the canonical interaction within the TZD binding site mediates classical PPARγ activation, the effects of the second binding on PPARγ activity remain elusive.

Development of a Potent Nurr1 Agonist Tool for In Vivo Applications.

Nuclear receptor related 1 (Nurr1) is a neuroprotective transcription factor and an emerging target in neurodegenerative diseases. Despite strong evidence for a role in Parkinson's and Alzheimer's disease, pharmacological control and validation of Nurr1 are hindered by a lack of suitable ligands. We have discovered considerable Nurr1 activation by the clinically studied dihydroorotate dehydrogenase (DHODH) inhibitor vidofludimus calcium and systematically optimized this scaffold to a Nurr1 agonist with nanomolar potency, strong activation efficacy, and pronounced preference over the highly related receptors Nur77 and NOR1.

Tubular Epithelial Cell HMGB1 Promotes AKI-CKD Transition by Sensitizing Cycling Tubular Cells to Oxidative Stress: A Rationale for Targeting HMGB1 during AKI Recovery.

Significance Statement: Cells undergoing necrosis release extracellular high mobility group box (HMGB)-1, which triggers sterile inflammation upon AKI in mice. Neither deletion of HMGB1 from tubular epithelial cells, nor HMGB1 antagonism with small molecules, affects initial ischemic tubular necrosis and immediate GFR loss upon unilateral ischemia/reperfusion injury (IRI). On the contrary, tubular cell-specific HMGB1 deficiency, and even late-onset pharmacological HMGB1 inhibition, increased functional and structural recovery from AKI, indicating that intracellular HMGB1 partially counters the effects of extracellular HMGB1.

Fragment-based discovery of orphan nuclear receptor Nur77/NGFI-B ligands.

The transcription factor nerve growth factor-induced clone B (NGFI-B, Nur77, NR4A1) is an orphan nuclear receptor playing a role in cell survival and apoptosis regulation. Pharmacological Nur77 modulation holds promise for cancer and (neuro-)inflammatory disease treatment. The available Nur77 ligand scaffolds based on highly lipophilic natural products cytosporone B, celastrol and isoalantolactone are inadequate for the development of potent Nur77 modulators with favorable properties as chemical tools and future drugs.

Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists.

Fatty acid mimetics (FAM) are bioactive molecules acting through the binding sites of endogenous fatty acid metabolites on enzymes, transporters, and receptors. Due to the special characteristics of these binding sites, FAMs share common chemical features. Pharmacological modulation of fatty acid signaling has therapeutic potential in multiple pathologies, and several FAMs have been developed as drugs.

Druggability Evaluation of the Neuron Derived Orphan Receptor (NOR-1) Reveals Inverse NOR-1 Agonists.

The neuron derived orphan receptor (NOR-1, NR4A3) is among the least studied nuclear receptors. Its physiological role and therapeutic potential remain widely elusive which is in part due to the lack of chemical tools that can directly modulate NOR-1 activity. To probe the possibility of pharmacological NOR-1 modulation, we have tested a drug fragment library for NOR-1 activation and repression.

Nurr1 Modulation Mediates Neuroprotective Effects of Statins.

The ligand-sensing transcription factor Nurr1 emerges as a promising therapeutic target for neurodegenerative pathologies but Nurr1 ligands for functional studies and therapeutic validation are lacking. Here pronounced Nurr1 modulation by statins for which clinically relevant neuroprotective effects are demonstrated, is reported. Several statins directly affect Nurr1 activity in cellular and cell-free settings with low micromolar to sub-micromolar potencies.

Drug Testing for Residual Progression of Diabetic Kidney Disease in Mice Beyond Therapy with Metformin, Ramipril, and Empagliflozin.

Background: Progression of CKD in type 2 diabetes, despite dual inhibition of sodium-glucose transporter-2 and the renin-angiotensin system, remains a concern. Bromoindirubin-3'-oxime (BIO), previously reported to promote podocyte survival and regeneration, is a candidate additional drug to elicit renoprotective effects beyond therapy with metformin, ramipril, and empagliflozin (MRE). Evaluating a drug with standard therapeutics more closely mimics the clinical setting than evaluating the drug alone.