Ligand Design

OBJECTIVE: The peroxisome proliferator-activated receptor α (PPARα) is a transcription factor driving target genes involved in fatty acid β-oxidation. To what extent various PPARα interacting proteins may assist its function as a transcription factor is incompletely understood. An ORFeome-wide unbiased mammalian protein-protein interaction trap (MAPPIT) using PPARα as bait revealed a PPARα-ligand-dependent interaction with the orphan nuclear receptor estrogen-related receptor α (ERRα)...

Recently, we have developed novel Pim-1 kinase inhibitors starting from a dihydrobenzofuran core structure using a computational approach. Here, we report the design and synthesis of stilbene-based Pim-1 kinase inhibitors obtained by formal elimination of the dihydrofuran ring. These inhibitors of the first design cycle, which were obtained as inseparable cis/trans mixtures, showed affinities in the low single-digit micromolar range. To be able to further optimize these compounds in a structure-based fashion, we determined the X-ray structures of the protein-ligand-complexes...

Recently, there has been a notable surge in interest regarding reclaiming valuable chemicals from waste plastics. However, the energy-intensive conventional thermal catalysis does not align with the concept of sustainable development. Herein, we report a sustainable electrocatalytic approach allowing the selective synthesis of glycolic acid (GA) from waste polyethylene terephthalate (PET) over a Pd67 Ag33 alloy catalyst under ambient conditions. Notably, Pd67 Ag33 delivers a high mass activity of 9.7 A mgPd -1 for ethylene glycol oxidation reaction (EGOR) and GA Faradaic efficiency of 92...

Revealing protein binding sites with other molecules, such as nucleic acids, peptides, or small ligands, sheds light on disease mechanism elucidation and novel drug design. With the explosive growth of proteins in sequence databases, how to accurately and efficiently identify these binding sites from sequences becomes essential. However, current methods mostly rely on expensive multiple sequence alignments or experimental protein structures, limiting their genome-scale applications. Besides, these methods haven't fully explored the geometry of the protein structures...

Exosomal programmed death ligand-1 (ExoPD-L1) is a vital marker of immune activation in the early stages of tumor therapy and it can inhibit anti-tumor immune responses. However, due to the low expression of ExoPD-L1 in cancer cells, it is difficult to perform highly sensitive assays and accurately differentiate cancer sources. Therefore, we constructed a coaxial dual-path electrochemical biosensor for highly accurate identification and detection of ExoPD-L1 from lung cancer based on chemical-biological coaxial nanomaterials and nucleic acid molecular signal amplification strategies...

Electrophilic small molecules with novel reactivity are powerful tools that enable activity-based protein profiling and covalent inhibitor discovery. Here, we report a reactive heterocyclic scaffold, 4-chloro-pyrazolopyridine (CPzP) for selective modification of proteins via a nucleophilic aromatic substitution (SN Ar) mechanism. Chemoproteomic profiling reveals that CPzPs engage cysteines within functionally diverse protein sites including ribosomal protein S5 (RPS5), inosine monophosphate dehydrogenase 2 (IMPDH2), and heat shock protein 60 (HSP60)...

BACKGROUND: The role of Forkhead Box D2 (FOXD2) in head and neck squamous cell carcinoma (HNSC) has never been studied. OBJECT: Our object was to explore the role of FOXD2 in HNSC. METHODS: Clinical data for patients with HNSC was obtained from TCGA. Our study examined the atypical expression of FOXD2 in both HNSC and pan-cancer, along with its diagnostic and prognostic implications, as well as the association between FOXD2 expression and clinical characteristics, immune infiltration, immune checkpoint genes, and MSI...

BACKGROUND: ChuShiWeiLing Decoction (CSWLD) is a famous classical Chinese prescription for the treatment of eczema with desirable effect in clinical practice. It has gradually exerted good curative effects on perianal eczema (PE) in recent years, but its specific mechanism is not elucidated yet. OBJECTIVE: This research explores the underlying pharmacological mechanism of CSWLD in addressing PE through network pharmacology combined with molecular docking strategy...

Ligand-binding assays (LBAs) rely on the reversible, noncovalent binding between the analyte of interest and the assay reagents, and understanding their dynamic equilibrium is key to building robust LBA methods. Although the dynamic interplay of free and bound fractions can be calculated using mathematical models, these are not routinely applied. This approach is costly in terms of both assay development time and reagents, and can result in an under-exploration of the possible parameter combinations. Therefore, we have created a user-friendly simulation tool to facilitate LBA development (the BiSim Tool)...

Peptide macrocycles have recently gained attention as protease inhibitors due to their metabolic stability and specificity. However, the development of peptide macrocycles with improved binding potency has so far been challenging. Here we present macrocyclic peptides derived from the clinically applied proteasome inhibitor carfilzomib with an oxindole group that mimics the natural product TMC-95A. Fluorescence kinetic activity assays reveal a high potency of the oxindole group (IC50 = 0.19 μM) compared with agents lacking this motif...

Small-molecule inhibitors targeting programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions can compensate for the shortcomings of antibody-based inhibitors and have attracted considerable attention, some of which have already entered clinical trials. Herein, based on our previous study on small-molecule PD-L1 inhibitors, we reported a series of 8-( o -tolyl)quinazoline derivatives by the skeleton merging strategy. Homogenous time-resolved fluorescence (HTRF) assay against PD-1/PD-L1 interaction identified compound A5 , which showed the most potent inhibition with an IC50 value of 23...

One of the worst long-term health issues of the past few decades is Alzheimer's disease (AD). Unfortunately, there are currently insufficient choices for treating and caring for AD, which makes it a popular subject for drug development research. Studies on the development of drugs for AD have primarily concentrated on the use of multitarget directed ligands. Following this strategy, we designed new ChE inhibitors with additional antioxidant and metal chelator effects. In this research, eight novel N'-(quinolin-4-ylmethylene)propanehydrazide derivatives were synthesized and characterized...

The adenosine A3 receptor (A3 AR), a key member of the G protein-coupled receptor family, is a promising therapeutic target for inflammatory and cancerous conditions. The selective A3 AR agonists, CF101 and CF102, are clinically significant, yet their recognition mechanisms remained elusive. Here we report the cryogenic electron microscopy structures of the full-length human A3 AR bound to CF101 and CF102 with heterotrimeric Gi protein in complex at 3.3-3.2 Å resolution. These agonists reside in the orthosteric pocket, forming conserved interactions via their adenine moieties, while their 3-iodobenzyl groups exhibit distinct orientations...

The direct double dehydrogenation from primary amines to nitriles without an oxidant or hydrogen acceptor is both intriguing and challenging. In this paper, we describe a non-noble metal catalyst capable of realizing such a transformation with high efficiency. A cobalt-centered N , N- bidentate complex was designed and employed as a metal-ligand cooperative dehydrogenation catalyst. Detailed kinetic studies, control experiments, and DFT calculations revealed the crucial hydride transfer, proton transfer, and hydrogen evolution processes...

Covid-19 disease caused by the deadly SARS-CoV-2 virus is a serious and threatening global health issue declared by the WHO as an epidemic. Researchers are studying the design and discovery of drugs to inhibit the SARS-CoV-2 virus due to its high mortality rate. The main Covid-19 virus protease (Mpro) and human transmembrane protease, serine 2 (TMPRSS2) are attractive targets for the study of antiviral drugs against SARS-2 coronavirus. Increasing consumption of herbal medicines in the community and a serious approach to these drugs have increased the demand for effective herbal substances...

Mitochondria are important drug targets for anticancer and other disease therapies. Certain human mitochondrial DNA sequences capable of forming G-quadruplex structures (G4s) are emerging drug targets of small molecules. Despite some mitochondria-selective ligands being reported for drug delivery against cancers, the ligand design is mostly limited to the triphenylphosphonium scaffold. The ligand designed with lipophilic small-sized scaffolds bearing multipositive charges targeting the unique feature of high mitochondrial membrane potential (MMP) is lacking and most mitochondria-selective ligands are not G4-targeting...

INTRODUCTION: RC98 is the monoclonal antibody against Programmed Cell Death Ligand 1 (PD-L1). Relevant reports have confirmed that the influence of PD-L1 expressed by tumor cells on antitumor CD8+ T cell responses is well characterized, but the impact of PD-L1 expressed by immune cells has not been well defined. OBJECTIVE: This study aimed to design a Pharmacokinetics/Pharmacology (PK/PD) study of RC98 in normal cynomolgus monkeys to research the effect on the immune system...

Foldamer is a scaled-down version of coil spring, which can absorb and release energy by conformational change. Here, polymer networks with high-density of molecular springs were developed by employing anion-coordination-based foldamers as the monomer. The coiling of the foldamer is controlled by oligourea ligands coordinating to chloride ions; subsequently, the folding and unfolding of foldamer conformations endow the polymer network with excellent energy dissipation and toughness. The mechanical performance of the corresponding polymer network shows a dramatic increase from P-L2UCl (non-folding), P-L4UCl (a full turn) to P-L6UCl (1...

Two monometallic and three bimetallic ruthenium acetonitrile (RuMeCN) complexes are presented and fully characterized. All of them are built from the same skeleton [FTRu(bpy)(MeCN)]2+ , in which FT is a fluorenyl-substituted terpyridine ligand and bpy is the 2,2'-bipyridine. The crystal structure of [FTRu(bpy)(MeCN)](PF6 )2 is presented. A careful spectroscopic analysis allows establishing that these 5 RuMeCN complexes can be identified as the product of the photoreaction of 5 related RuNO complexes, investigated as efficient nitric oxide (NO) donors...

Electrically conducting two-dimensional (2D) metal-organic frameworks (MOFs) have garnered significant interest due to their remarkable structural tunability and outstanding electrical properties. However, the design and synthesis of high-performance materials face challenges due to the limited availability of specific ligands and pore structures. In this study, we have employed a novel highly branched D3h symmetrical planar conjugated ligand, dodechydroxylhexabenzotrinaphthylene (DHHBTN) to fabricate a series of 2D conductive MOFs, named M-DHHBTN (M = Co, Ni, and Cu)...