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ABSTRACT This research article provides a comprehensive analysis of the preparation, structural characterization, 3D modeling, and biological screening of two novel formulated metal complexes, NiPDBZNPH and CuPDBZNPH. These complexes were obtained by combining 2,2′‐pyridine‐2,6‐diylbis(1H‐benzimidazole) (PDBZ) and 2‐hydroxy‐naphthaldehyde Schiff‐base (NPH) ligands with Ni(II) and Cu(II) ions, resulting in the compounds [Ni (NPH)(PDBZ)(Cl)] and [Cu (NPH)(PDBZ)(Cl)], respectively. Spectroscopic and analytical techniques confirmed that both complexes exhibit octahedral geometry around the central metal ion. Computational studies using density functional theory (DFT) corroborated the molecular structures and investigated the quantum chemical properties of the ligands and complexes. A series of in vitro assays were conducted to assess their anti‐inflammatory, antifungal, antibacterial, and antioxidant properties, revealing enhanced bioactivity compared to the uncoordinated ligands. The potential of NiPDBZNPH and CuPDBZNPH as therapeutic candidates was also explored through interactions with calf thymus DNA (CT‐DNA). Molecular docking simulations targeting specific protein receptors were performed to evaluate binding affinities and ligand–protein interactions, with results highlighting significant interactions within enzyme active sites. These findings emphasize the pivotal role of metal–ligand coordination in enhancing pharmacological properties and contribute valuable insights toward the design of novel therapeutic compounds for use in medicinal chemistry and pharmaceutical research. [ABSTRACT FROM AUTHOR]

Herein, we have demonstrated a palladium‐catalyzed γ‐alkenylation of unactivated alkenes with vinylcyclopropanes. A bidentate 8‐aminoquinoline directing group was utilized for the regioselective γ‐C(alkenyl)−H functionalization of unactivated alkenes with vinylcyclopropanes. This protocol exhibits wide substrate scope and good selectivity. Additionally, substrate diversification was performed to demonstrate the synthetic utility of the protocol. Mechanistic investigations were carried out to provide an insight to the reaction mechanism. A plausible mechanism was also proposed for the present methodology. [ABSTRACT FROM AUTHOR]

Aggregated forms of different proteins are common hallmarks for several neurodegenerative diseases, including Alzheimer's disease, and ligands that selectively detect specific protein aggregates are vital. Herein, we investigate the molecular requirements of thiophene‐vinyl‐benzothiazole based ligands to detect a specific type of Aβ deposits found in individuals with dominantly inherited Alzheimer's disease caused by the Arctic APP E693G mutation. The staining of these Aβ deposits was alternated when switching the terminal heterocyclic moiety attached to the thiophene‐vinyl‐benzothiazole scaffold. The most prevalent staining was observed for ligands having a terminal 3‐methyl‐1H‐indazole moiety or a terminal 1,2‐dimethoxybenzene moiety, verifying that specific molecular interactions between these ligands and the aggregates were necessary. The synthesis of additional thiophene‐vinyl‐benzothiazole ligands aided in pinpointing additional crucial chemical determinants, such as positioning of nitrogen atoms and methyl substituents, for achieving optimal staining of Aβ aggregates. When combining the optimized thiophene‐vinyl‐benzothiazole based ligands with a conventional ligand, CN‐PiB, distinct staining patterns were observed for sporadic Alzheimer's disease versus dominantly inherited Alzheimer's disease caused by the Arctic APP E693G mutation. Our findings provide chemical insights for developing novel ligands that allow for a more precise assignment of Aβ deposits, and might also aid in creating novel agents for clinical imaging of distinct Aβ aggregates in AD. [ABSTRACT FROM AUTHOR]

In this research work, the catalytic performances of two manganese-based catalysts, manganese (III) acetylacetonate (Mn(acac)3) and manganese tallate (Mn-TO), were studied during the process of Ashalcha heavy oil oxidation under in situ combustion conditions. DSC analysis shows distinct thermal behavior of both ligated catalysts during low- and high-temperature oxidation phases (LTO and HTO); for example, the shifting in peak temperature (Tp) in the HTO at a heating rate of 10 °C/min was reduced by approximately 5.3% for Mn-TO and 2.24% for Mn(acac)3 when compared with uncatalyzed heavy oil. Combined isothermal kinetic analyses using the Friedman and Kissinger–Akahira–Sunose analytic methods have provided insights about activation energies and frequency factors over the whole conversion range, where the catalytic performance of Mn-TO showed low activation energies in both LTO and HTO (Eα of Mn-TO was approximately 13.33% (LTO) and 7.68% (HTO) less than with the heavy oil alone). In addition, calculations of the effective rate constant confirmed the increased oxidation rate trend of both catalysts, with Mn-TO exhibiting the highest values. The findings highlight the potential of these manganese-based catalysts, the Mn-TO catalyst in particular, in optimizing heavy oil oxidation processes. The overall results further contribute to developing more efficient ligand catalyst complexes for sustainable heavy oil recovery while continuously improving their efficient application during in situ combustion in the petroleum industry. [ABSTRACT FROM AUTHOR]

AbstractMethane activation and functionalization under catalytic conditions remains a challenge that must be addressed to make this abundant alkane, the primary component of natural gas, into a more useful resource. One possible method of methane activation is concerted metalation-deprotonation (CMD), which thus far has been largely limited to precious metals and more reactive substrates. In this DFT study, CMD activation of methane is assessed employing more earth-abundant 3d transition metal complexes to assess the effects of metal, ligands, etc. upon the kinetics and thermodynamics of methane C–H activation via CMD mechanisms. Key findings from this study reveal the strong influence spin states as well as ligand modification have on the activation energy barriers. Moreover, an unexpected observation pertaining to ligand modification was seen where the acetate ligand exhibited higher computed free energy barriers compared to the trifluoroacetate ligand. Although acetate is more basic than trifluoroacetate, the ligand directing effects ultimately had a greater influence on the thermodynamic control of the CMD mechanism being studied here. [ABSTRACT FROM AUTHOR]

Stem cell factors (SCFs) are pivotal factors existing in both soluble and membrane-bound forms, expressed by endothelial cells (ECs) and fibroblasts throughout the body. These factors enhance cell growth, viability, and migration in multipotent cell lineages. The preferential expression of SCF by arteriolar ECs indicates that arterioles create a unique microenvironment tailored to hematopoietic stem cells (HSCs). Insufficiency of SCF within bone marrow (BM)-derived adipose tissue results in decreased their overall cellularity, affecting HSCs and their immediate progenitors critical for generating diverse blood cells and maintaining the hematopoietic microenvironment. SCF deficiency disrupts BM function, impacting the production and differentiation of HSCs. Additionally, deleting SCF from adipocytes reduces lipogenesis, highlighting the crucial role of SCF/c-kit signaling in controlling lipid accumulation. This review elucidates the sources, roles, mechanisms, and molecular strategies of SCF in bone renewal, offering a comprehensive overview of recent advancements, challenges, and future directions for leveraging SCF as a key agent in regenerative medicine. [ABSTRACT FROM AUTHOR]

We have explored NHSi‐supported copper(I) complexes as active and highly efficient catalysts for A3 (aldehyde‐alkyne‐amine) and KA2 (ketone‐alkyne‐amine) three‐component coupling reactions to synthesize propargyl amines in excellent yields with high TOF under solvent‐and additive‐free conditions. [ABSTRACT FROM AUTHOR]

Nanoparticle-based thin films are increasingly being used in various applications. One of the key factors that determines the properties and performances of these films is the type of ligands attached to the nanoparticle surfaces. While long-chain surfactants, such as oleic acid, are commonly employed to stabilize nanoparticles and ensure high monodispersity, these ligands often hinder charge transport due to their insulating nature. Although thermal annealing can remove the long-chain ligands, the removal process often introduces defects such as cracks and voids. In contrast, the use of short-chain organic or inorganic ligands can minimize interparticle distance, improving film conductivity, though challenges such as incomplete ligand exchange and residual barriers remain. Polymeric ligands, especially block copolymers, can also be employed to create films with tailored porosity. This review discusses the effects of various ligand types on the morphology and performance of nanoparticle-based films, highlighting the trade-offs between conductivity, structural integrity, and functionality. [ABSTRACT FROM AUTHOR]

This article provides a comprehensive examination of non-canonical DNA structures, particularly focusing on G-quadruplexes (G4s) and i-motifs. G-quadruplexes, four-stranded structures formed by guanine-rich sequences, are stabilized by Hoogsteen hydrogen bonds and monovalent cations like potassium. These structures exhibit diverse topologies and are implicated in critical genomic regions such as telomeres and promoter regions of oncogenes, playing significant roles in gene expression regulation, genome stability, and cellular aging. I-motifs, formed by cytosine-rich sequences under acidic conditions and stabilized by hemiprotonated cytosine–cytosine (C:C+) base pairs, also contribute to gene regulation despite being less prevalent than G4s. This review highlights the factors influencing the stability and dynamics of these structures, including sequence composition, ionic conditions, and environmental pH. Molecular dynamics simulations and high-resolution structural techniques have been pivotal in advancing our understanding of their folding and unfolding mechanisms. Additionally, the article discusses the therapeutic potential of small molecules designed to selectively bind and stabilize G4s and i-motifs, with promising implications for cancer treatment. Furthermore, the structural properties of these DNA forms are explored for applications in nanotechnology and molecular devices. Despite significant progress, challenges remain in observing these structures in vivo and fully elucidating their biological functions. The review underscores the importance of continued research to uncover new insights into the genomic roles of G4s and i-motifs and their potential applications in medicine and technology. This ongoing research promises exciting developments in both basic science and applied fields, emphasizing the relevance and future prospects of these intriguing DNA structures. [ABSTRACT FROM AUTHOR]

Objective: To investigate the associations between apparent diffusion coefficient (ADC) values extracted from three different region of interest (ROI) position approaches and programmed cell death ligand-1 (PD-L1) expression, and evaluate the performance of the nomogram established based on ADC values and clinicopathological parameters in predicting PD-L1 expression in cervical cancer (CC) patients. Methods: Through retrospective recruitment, a training cohort of 683 CC patients was created, and a validation cohort of 332 CC patients was prospectively recruited. ROIs were delineated using three different methods to measure the mean ADC (ADCmean), single-section ADC (ADCss), and the minimum ADC of tumors (ADCmin). Logistic regression was employed to identify independent factors related to PD-L1 expression. A nomogram was drawn based on ADC values combined with clinicopathological features, its discrimination and calibration performances were estimated using the area under the curve (AUC) of receiver operating characteristic and calibration curve. The clinical benefits were evaluated by decision curve analysis. Results: The ADCmin independently correlated with PD-L1 expression. The nomogram constructed with ADCmin and other independent clinicopathological-related factors: FIGO staging, pathological grade, parametrial invasion, and lymph node status demonstrated excellent diagnostic performance (AUC = 0.912 and 0.903, respectively), good calibration capacities, and greater net benefits compared to the clinicopathological model in both the training and validation cohorts. Conclusion: ADCmin independently correlated PD-L1 expression, and the nomogram established with ADCmin and clinicopathological independent prognostic factors had a strong predictive performance for PD-L1 expression, thereby serving as a promising tool for selecting cases eligible for immunotherapy. Clinical relevance statement: The minimum ADC can serve as a reliable imaging biomarker related to PD-L1 expression; the established nomogram combines the minimum ADC and clinicopathological factors that can assist clinical immunotherapy decisions. Key Points: Diffusion-weighted imaging quantitative parameters can characterize the internal characteristics of tumor tissue. The minimum ADC significantly correlated with programmed cell death ligand-1 expression. The proposed nomogram can assist clinicians with immunotherapy decision-making for patients with CC. [ABSTRACT FROM AUTHOR]

γ‐Hydroxybutyric acid (GHB) analogs are small molecules that bind competitively to a specific cavity in the oligomeric CaMKIIα hub domain. Binding affects conformation and stability of the hub domain, which may explain the neuroprotective action of some of these compounds. Here, we describe molecular details of interaction of the larger‐type GHB analog 2‐(6‐(4‐chlorophenyl)imidazo[1,2‐b]pyridazine‐2‐yl)acetic acid (PIPA). Like smaller‐type analogs, PIPA binding to the CaMKIIα hub domain promoted thermal stability. PIPA additionally modulated CaMKIIα activity under sub‐maximal CaM concentrations and ultimately led to reduced substrate phosphorylation. A high‐resolution X‐ray crystal structure of a stabilized CaMKIIα (6x mutant) hub construct revealed details of the binding mode of PIPA, which involved outward placement of tryptophan 403 (Trp403), a central residue in a flexible loop close to the upper hub cavity. Small‐angle X‐ray scattering (SAXS) solution structures and mass photometry of the CaMKIIα wild‐type hub domain in the presence of PIPA revealed a high degree of ordered self‐association (stacks of CaMKIIα hub domains). This stacking neither occurred with the smaller compound 3‐hydroxycyclopent‐1‐enecarboxylic acid (HOCPCA), nor when Trp403 was replaced with leucine (W403L). Additionally, CaMKIIα W403L hub was stabilized to a larger extent by PIPA compared to CaMKIIα hub wild type, indicating that loop flexibility is important for holoenzyme stability. Thus, we propose that ligand‐induced outward placement of Trp403 by PIPA, which promotes an unforeseen mechanism of hub domain stacking, may be involved in the observed reduction in CaMKIIα kinase activity. Altogether, this sheds new light on allosteric regulation of CaMKIIα activity via the hub domain. [ABSTRACT FROM AUTHOR]

Transient melting of the duplex‐DNA (B‐DNA) during DNA transactions allows repeated sequences to fold into non‐B‐DNA structures, including DNA junctions and G‐quadruplexes. These noncanonical structures can act as impediments to DNA polymerase progression along the duplex, thereby triggering DNA damage and ultimately jeopardizing genomic stability. Their stabilization by ad hoc ligands is currently being explored as a putative anticancer strategy since it might represent an efficient way to inflict toxic DNA damage specifically to rapidly dividing cancer cells. The relevance of this strategy is only emerging for three‐way DNA junctions (TWJs) and, to date, no molecule has been recognized as a reference TWJ ligand, featuring both high affinity and selectivity. Herein, we characterize such reference ligands through a combination of in vitro techniques comprising affinity and selectivity assays (competitive FRET‐melting and TWJ Screen assays), functional tests (qPCR and Taq stop assays) and structural analyses (molecular dynamics and NMR investigations). We identify novel azacryptands TrisNP‐amphi and TrisNP‐ana as the most promising ligands, interacting with TWJs with high affinity and selectivity. These ligands represent new molecular tools to investigate the cellular roles of TWJs and explore how they can be exploited in innovative anticancer therapies. [ABSTRACT FROM AUTHOR]

Six new complexes (1–6), [Ru(η6‐p‐cymene)(FA)Cl] (1), [Ru(η6‐p‐cymene)(PA)Cl] (2), [Ru(η6‐p‐cymene)(SA)Cl] (3), [Ru(η6‐p‐cymene)(FA)PPh3]Cl (4), [Ru(η6‐p‐cymene)(PA)PPh3]Cl (5), [Ru(η6‐p‐cymene)(SA)PPh3]Cl(6), [HFA = ferulic acid, HPA = p‐coumaric acid, HSA = sinapinic acid], were synthesized and well characterized by various spectroscopic, analytical techniques and computational studies. Amongst these six complexes, complexes 4, 5, and 6 were found to be selectively cytotoxic toward melanoma (A375) cell lines and were non‐cytotoxic toward non‐cancerous cell lines (HEK 293 T). Further investigation on the probable bio‐molecular interaction mechanisms revealed that all the complexes show strong groove binding interactions with the DNA, however, complexes 3, 4 and 3, 6 show strong interaction with BSA and HSA, respectively. Through Hoechst staining it can be elucidated that complexes 4–6 cause characteristic apoptotic nuclear changes in the cells indicating apoptosis as the cell death mechanism caused by complexes 4–6. To further confirm the cell death mechanism, protein expression analysis was done through western blotting, which showed a decrease in anti‐apoptotic protein (Bcl‐xL) expression and increased pro‐apoptotic protein (PARP) expression, which confirms the cell death by apoptosis. Using DCFDA staining, we observed that complexes 4, 5, and 6 produced more ROS in the cells, which also might be the cause of cell death by the complexes. Along with that the complexes show enhanced anti‐migratory abilities depicted through wound healing assay. [ABSTRACT FROM AUTHOR]

Selenium-based nanoparticles exhibit antiviral activity by directly modulating immune function. Despite recent promising developments in utilizing selenium nanoparticles (Se NPs) against viral infections, the impact of surface ligand charge on the conformation and interaction with viral proteins, as well as the effectiveness of Se NPs in anti-Herpes simplex virus 1 (HSV-1) infection remains unexplored. In this study, three types of selenium nanoparticles (CTAB-Se, PVP-Se, SDS-Se) with distinct surface charges were synthesized by modifying the surface ligands. We found that apart from differences in surface charge, the size, morphology, and crystal structure of the three types of Se NPs were similar. Notably, although the lipophilicity and cellular uptake of SDS-Se with a negative charge were lower compared to positively charged CTAB-Se and neutrally charged PVP-Se, SDS-Se exhibited the strongest protein binding force during interaction with HSV-1. Consequently, SDS-Se demonstrated the most potent anti-HSV-1 activity and safeguarded normal cells from damage. The mechanistic investigation further revealed that SDS-Se NPs effectively inhibited the proliferation and assembly of HSV-1 by powerfully suppressing the key genes and proteins of HSV-1 at various stages of viral development. Hence, this study highlights the significant role of surface ligand engineering in the antiviral activity of Se NPs, presenting a viable approach for synthesizing Se NPs with tailored antiviral properties by modulating surface charge. This method holds promise for advancing research on the antiviral capabilities of Se NPs. [ABSTRACT FROM AUTHOR]

Methanol is gaining popularity as a transfer-hydrogenating agent in catalytic reduction reactions because of its bulk-scale production and inexpensive nature. Current research interests include the utilization of methanol as a safe and sustainable hydrogen source for chemical synthesis and drug development. In particular, the chemoselective reduction of α,β-unsaturated ketones is of great interest because of their prevalence in many natural products. We investigated the potential application of acridine-derived SNS-Ru pincer complexes in methanol activation for chemoselective reduction of chalcones. Our developed catalytic system showed broad substrate tolerance, including substrates containing reducible functional groups. Control experiments and postsynthetic applications are also highlighted. [ABSTRACT FROM AUTHOR]

Molecular docking simulations were conducted to analyze the interactions between eight lead molecules with AR and PSA proteins. The lead molecules included Enzalutamide, Abiraterone, Docetaxel, Apalutamide, Cabazitaxel, Bicalutamide, Curcumin, Galeterone, Resveratrol, and Darolutamide. For the Androgen Receptor (AR), Enzalutamide displayed the most favorable docking energy of -10.96Kcal/mol, followed by Galeterone (-10.52Kcal/mol) and Darolutamide (-9.97Kcal/mol). The binding affinities of these compounds to AR suggest potential inhibitors. On the other hand, resveratrol exhibited the strongest interaction with the AR protein (-8.02Kcal.mol) among the natural compounds studied (Resveratrol and Curcumin). In the case of Prostate Specific Antigen (PSA), Abiraterone showed a docking energy of -9.14 kcal/mol, indicating a potential interaction with PSA. The docking results suggest that Enzalutamide, Galeterone, and Darolutamide, hold promise as potential inhibitors for the Androgen Receptor in prostate cancer treatment. Abiraterone, Enzalutamide, Apalutamide ligands shown a significant interaction on Prostate Specific Antigen, hinting at its potential as a dual-target agent.

Background: New Delhi metallo-beta-lactamase-1 (NDM1) confers resistance to several bacterial species against a broad range of beta-lactam antibiotics and turning them into superbugs that pose a significant threat to healthcare systems worldwide. As such, it is a potentially relevant biological target for counteracting bacterial infections. Given the lack of effective treatment options against NDM1 producing bacteria, finding a reliable inhibitor for the NDM1 enzyme is crucial. Methods: Using molecular dynamics simulations, the binding selectivities and affinities of three ligands, viz. PNK, 3S0, and N1G were investigated against NDM1. Results: The results indicate that N1G binds with more affinity to NDM1 than PNK and 3S0. The binding energy decomposition analysis revealed that residues I35, W93, H189, K211, and N220 showed significant binding energies with PNK, 3S0, and N1G, and hence are crucially involved in the binding of the ligands to NDM1. Molecular dynamics trajectory analysis further elicited that the ligands influence dynamic flexibility of NDM1 morphology, which contributes to the partial selectivities of PNK, 3S0, and N1G. Conclusions: This in silico study offers a vital information for developing potential NDM1 inhibitors with high selectivity. Nevertheless, in vitro and in vivo experimental validation is mandated to extend the possible applications of these ligands as NDM1 inhibitors that succor in combating antimicrobial resistance.

Coordination compounds are molecules that contain one or more metal centers bound to ligands. Ligands can be atoms, ions, or molecules that transfer electrons to the metal. These compounds can be charged or neutral. When charged, neighboring counter-ions help stabilize the complex. The metal ion is located at the center of a complex ion, surrounded by other molecules or ions known as ligands. Ligands can be thought of as covalently bonded to the core ion through coordination. Understanding coordination theory in chemistry provides insight into the geometric shape of complexes and the structure of coordination compounds, which consist of a central atom or molecule connected to surrounding atoms or compounds. Inorganic coordination compounds exhibit different properties and are used in synthesizing organic molecules. The coordination of chemicals is vital for the survival of living organisms. Metal complexes are also essential for various biological processes, with many enzymes, known as metalloenzymes, being composed of metal complexes. These metal complexes occur naturally. [ABSTRACT FROM AUTHOR]

This review focuses on functional materials that contain terpyridine (terpy) units, which can be synthesized from biomass-derived platform chemicals. The latter are obtained by the chemical conversion of raw biopolymers such as cellulose (e.g., 2-furaldehyde) or lignin (e.g., syringaldehyde). These biomass-derived platform chemicals serve as starting reagents for the preparation of many different terpyridine derivatives using various synthetic strategies (e.g., Kröhnke reaction, cross-coupling reactions). Chemical transformations of these terpyridines provide a broad range of different ligands with various functionalities to be used for the modification or construction of various materials. Either inorganic materials (such as oxides) or organic ones (such as polymers) can be combined with terpyridines to provide functional materials. Different strategies are presented for grafting terpy to materials, such as covalent grafting through a carboxylic acid or silanization. Furthermore, terpy can be used directly for the elaboration of functional materials via complexation with metals. The so-obtained functional materials find various applications, such as photovoltaic devices, heterogeneous catalysts, metal–organic frameworks (MOF), and metallopolymers. Finally, some possible developments are presented. [ABSTRACT FROM AUTHOR]

Nuclear hormone receptors (NHRs) are a family of ligand-regulated transcription factors that control key aspects of development and physiology. The regulation of NHRs by ligands derived from metabolism or diet makes them excellent pharmacological targets, and the mechanistic understanding of how NHRs interact with their ligands to regulate downstream gene networks, along with the identification of ligands for orphan NHRs, could enable innovative approaches for cellular engineering, disease modeling and regenerative medicine. We review recent discoveries in the identification of physiologic ligands for NHRs. We propose new models of ligand-receptor co-evolution, the emergence of hormonal function and models of regulation of NHR specificity and activity via one-ligand and two-ligand models as well as feedback loops. Lastly, we discuss limitations on the processes for the identification of physiologic NHR ligands and emerging new methodologies that could be used to identify the natural ligands for the remaining 17 orphan NHRs in the human genome. [ABSTRACT FROM AUTHOR]

The aim of this study was to review the literature to explore the lipid-based drug delivery systems that have been investigated for improved treatment of lung cancers. Such lipid-based drug delivery systems include microemulsions, liposomes, transferosomes, niosomes, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). In order to minimise the side effects of chemotherapeutic active pharmaceutical ingredients, surface modification with various ligands has been introduced so that the delivery system will attach only to specific receptors which are overexpressed in lung cancer cells. This review briefly explored cancers and their aetiologies and risk factors, especially lung cancer. It then discussed different modifications that have been performed on the drug delivery systems to successfully treat lung cancer. The use of different ligands has also been investigated in this review. The particle size of drug delivery systems after the attachment of the ligand remained small, varying from 75 to 189 nm, which was the most significant physicochemical property during development as it affected the delivery of particles to specific sites in the lungs. Overall, evidence suggests that surface modified lipid-based drug delivery systems have significant potential to revolutionise the treatment of lung cancer, leading to reduced side effects from chemotherapy. [ABSTRACT FROM AUTHOR]

G protein‐coupled receptor (GPCR) activation initiates signalling via a complex network of intracellular effectors that combine to produce diverse cellular and tissue responses. Although we have an advanced understanding of the proximal events following receptor stimulation, the molecular detail of GPCR signalling further downstream often remains obscure. Unravelling these GPCR‐mediated signalling networks has important implications for receptor biology and drug discovery. In this context, phosphoproteomics has emerged as a powerful approach for investigating global GPCR signal transduction. Here, we provide a brief overview of the phosphoproteomic workflow and discuss current limitations and future directions for this technology. By highlighting some of the novel insights into GPCR signalling networks gained using phosphoproteomics, we demonstrate the utility of global phosphoproteomics to dissect GPCR signalling networks and to accelerate discovery of new targets for therapeutic development. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein‐Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc [ABSTRACT FROM AUTHOR]

This article discusses the synthesis of a new P-chiral phospholene core-based ligand called LemPhos. The authors propose a method using a chiral diene to create diastereomers that are easier to separate, allowing for the production of P-chiral ligands. The ligands are synthesized and characterized, and their application as catalysts in asymmetric hydrogenation reactions is explored. The document also includes experimental procedures and spectroscopic data for the synthesized compounds. The research is dedicated to the memory of Stanisław Lem, a renowned science-fiction writer. [Extracted from the article]

The importance of deuterium labelling in a variety of applications, ranging from mechanistic studies to drug‐discovery, has spurred immense interest in the development of new methods for its efficient incorporation in organic, and especially in bioactive molecules. The five‐membered heteroarenes at the center of this work are ubiquitous motifs in bioactive molecules and efficient methods for the deuterium labelling of these compounds are therefore highly desirable. However, the profound differences in chemical properties encountered between different heteroarenes hamper the development of a single set of broadly applicable reaction conditions, often necessitating a separate optimization campaign for a given type of heteroarene. In this study we describe the use of a multi‐substrate screening approach to identify optimal reaction conditions for different classes of heteroarenes from a minimal number of screening reactions. Using this approach, four sets of complementary reaction conditions derived from our dual ligand‐based palladium catalysts for nondirected C(sp2)−H activation were identified, that together enable the deuteration of structurally diverse heteroarenes, including bioactive molecules. [ABSTRACT FROM AUTHOR]

A facile synthetic approach is reported toward ligands based on 2-(2-pyridyl)quinazoline, which are suitable for the preparation of both water-soluble and liposoluble chelate complexes with lanthanide(iii) cations. The ligands contain an additional rigid chelating moiety, such as the carboxyl group or the diethylenetriaminetetraacetic acid residue. The luminescence properties of the new cationic EuIII and TbIII complexes were studied. [ABSTRACT FROM AUTHOR]

Molecular docking simulations were conducted to analyze the interactions between eight lead molecules with AR and PSA proteins. The lead molecules included Enzalutamide, Abiraterone, Docetaxel, Apalutamide, Cabazitaxel, Bicalutamide, Curcumin, Galeterone, Resveratrol, and Darolutamide. For the Androgen Receptor (AR), Enzalutamide displayed the most favorable docking energy of -10.96Kcal/mol, followed by Galeterone (-10.52Kcal/mol) and Darolutamide (-9.97Kcal/mol). The binding affinities of these compounds to AR suggest potential inhibitors. On the other hand, resveratrol exhibited the strongest interaction with the AR protein (-8.02Kcal.mol) among the natural compounds studied (Resveratrol and Curcumin). In the case of Prostate Specific Antigen (PSA), Abiraterone showed a docking energy of -9.14 kcal/mol, indicating a potential interaction with PSA. The docking results suggest that Enzalutamide, Galeterone, and Darolutamide, hold promise as potential inhibitors for the Androgen Receptor in prostate cancer treatment. Abiraterone, Enzalutamide, Apalutamide ligands shown a significant interaction on Prostate Specific Antigen, hinting at its potential as a dual-target agent. [ABSTRACT FROM AUTHOR]

The conceptual replacement of nitrogen with phosphorus in common organic functional groups unlocks new properties and reactivity. The phosphorus‐containing analogues of triazenes are underexplored but offer great potential as flexible and small bite‐angle ligands. This manuscript explores the synthesis and characterisation of a family of air‐stable azophosphine‐borane complexes, and their subsequent deprotection to the free azophosphines. These compounds are structurally characterised, both experimentally and computationally, and highlight the availability of the phosphorus lone pair for coordination. This is confirmed by demonstrating that neutral azophosphines can act as ligands in Ru complexes, and can coordinate as monodentate or bidentate ligands in a controlled manner, in contrast to their nitrogen analogues. [ABSTRACT FROM AUTHOR]

Triazaphospholes are potential polydentate ligands due to the presence of both phosphorus and nitrogen donor atoms within the aromatic 5‐membered heterocycle. The incorporation of an additional pyridyl‐substituent opens up the possibility of a post‐synthesis modification via chemoselective and also stepwise alkylation exclusively of the nitrogen atoms. This can be controlled by the choice and by the stoichiometry of the electrophile and allows the targeted synthesis of a variety of novel mono‐ and dicationic ligands. Reaction with Cu(I)‐halides causes the formation of cuprates of the type [CuXn](n−1)−, which enables coordination of the π‐acidic phosphorus donor to the negatively charged metal core, which is favored over the coordination by a strongly σ‐donating nitrogen atom. The use of cationic triazaphosphole derivatives can be used as a strategy to enforce the coordination of the ligand to an electron rich metal solely via the phosphorus atom. However, there is a subtle balance between the formation of either coordination polymers or dimeric structures, as the substitution pattern on the heterocycle and the nature of the halide have a large influence on the coordination motifs formed. [ABSTRACT FROM AUTHOR]

Nuclear hormone receptors exist in dynamic equilibrium between transcriptionally active and inactive complexes dependent on interactions with ligands, proteins, and chromatin. The present studies examined the hypothesis that endogenous ligands activate peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in keratinocytes. The phorbol ester treatment or HRAS infection of primary keratinocytes increased fatty acids that were associated with enhanced PPARβ/δ activity. Fatty acids caused PPARβ/δ-dependent increases in chromatin occupancy and the expression of angiopoietin-like protein 4 (Angptl4) mRNA. Analyses demonstrated that stearoyl Co-A desaturase 1 (Scd1) mediates an increase in intracellular monounsaturated fatty acids in keratinocytes that act as PPARβ/δ ligands. The activation of PPARβ/δ with palmitoleic or oleic acid causes arrest at the G2/M phase of the cell cycle of HRAS-expressing keratinocytes that is not found in similarly treated HRAS-expressing Pparb/d-null keratinocytes. HRAS-expressing Scd1-null mouse keratinocytes exhibit enhanced cell proliferation, an effect that is mitigated by treatment with palmitoleic or oleic acid. Consistent with these findings, the ligand activation of PPARβ/δ with GW0742 or oleic acid prevented UVB-induced non-melanoma skin carcinogenesis, an effect that required PPARβ/δ. The results from these studies demonstrate that PPARβ/δ has endogenous roles in keratinocytes and can be activated by lipids found in diet and cellular components. [ABSTRACT FROM AUTHOR]

New Delhi metallo-beta-lactamase-1 (NDM1) confers resistance to several bacterial species against a broad range of beta-lactam antibiotics and turning them into superbugs that pose a significant threat to healthcare systems worldwide. As such, it is a potentially relevant biological target for counteracting bacterial infections. Given the lack of effective treatment options against NDM1 producing bacteria, finding a reliable inhibitor for the NDM1 enzyme is crucial. Using molecular dynamics simulations, the binding selectivities and affinities of three ligands, viz. PNK, 3S0, and N1G were investigated against NDM1. The results indicate that N1G binds with more affinity to NDM1 than PNK and 3S0. The binding energy decomposition analysis revealed that residues I35, W93, H189, K211, and N220 showed significant binding energies with PNK, 3S0, and N1G, and hence are crucially involved in the binding of the ligands to NDM1. Molecular dynamics trajectory analysis further elicited that the ligands influence dynamic flexibility of NDM1 morphology, which contributes to the partial selectivities of PNK, 3S0, and N1G. This in silico study offers a vital information for developing potential NDM1 inhibitors with high selectivity. Nevertheless, in vitro and in vivo experimental validation is mandated to extend the possible applications of these ligands as NDM1 inhibitors that succor in combating antimicrobial resistance. [ABSTRACT FROM AUTHOR]

The foodborne pathogenic bacterium Campylobacter jejuni utilizes chemotaxis to assist in the colonization of host niches. A key to revealing the relationship among chemotaxis and pathogenicity is the discovery of signaling molecules perceived by the chemoreceptors. The C. jejuni chemoreceptor Tlp11 is encoded by the highly infective C. jejuni strains. In the present study, we report that the dCache-type ligand-binding domain (LBD) of C. jejuni ATCC 33560 Tlp11 binds directly to novel ligands methyl pyruvate, toluene, and quinoline using the same pocket. Methyl pyruvate elicits a strong chemoattractant response, while toluene and quinoline function as the antagonists without triggering chemotaxis. The sensory LBD was used to control heterologous proteins by constructing chimeras, indicating that the signal induced by methyl pyruvate is transmitted across the membrane. In addition, bioinformatics and experiments revealed that the dCache domains with methyl pyruvate-binding sites and ability are widely distributed in the order Campylobacterales. This is the first report to identify the class of dCache chemoreceptors that bind to attractant methyl pyruvate and antagonists toluene and quinoline. Our research provides a foundation for understanding the chemotaxis and virulence of C. jejuni and lays a basis for the control of this foodborne pathogen. [ABSTRACT FROM AUTHOR]

This article explores the use of pyrazolopyridine ligands in transition-metal-catalyzed reactions. These ligands have a wide range of effects and have been used in various oxidative and reductive reactions, as well as in applications such as solar cells and organic light-emitting diodes. The article discusses the synthesis of these ligands and their role in facilitating the formation of C-C and C-heteroatom bonds. It also provides specific examples of their use in different catalytic reactions, highlighting the importance of ligand design. The article encourages further research into the potential of pyrazolopyridine ligands in catalytic processes. [Extracted from the article]

Background In KEYNOTE-355 (NCT02819518), the addition of pembrolizumab to chemotherapy led to statistically significant improvements in progression-free survival and overall survival in patients with advanced triple-negative breast cancer with tumor programmed cell death ligand 1 (PD-L1) combined positive score of at least 10. We report patient-reported outcomes from KEYNOTE-355. Methods Patients were randomly assigned 2:1 to pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus investigator's choice chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30), Breast Cancer–Specific Quality of Life Questionnaire, and EuroQol 5-Dimension questionnaire visual analog scale were prespecified. Patient-reported outcomes were analyzed for patients who received at least 1 dose of study treatment and completed at least 1 patient-reported outcome assessment. Changes in patient-reported outcome scores from baseline were assessed at week 15 (latest time point at which completion and compliance rates were at least 60% and at least 80%, respectively). Time to deterioration in patient-reported outcomes was defined as time to first onset of at least a 10-point worsening in score from baseline. Results Patient-reported outcome analyses included 317 patients with tumor PD-L1 combined positive score of at least 10 (pembrolizumab plus chemotherapy: n = 217; placebo plus chemotherapy: n = 100). There were no between-group differences in change from baseline to week 15 in QLQ-C30 global health status/quality of life (QOL; least-squares mean difference = −1.81, 95% confidence interval [CI] = −6.92 to 3.30), emotional functioning (least-squares mean difference = −1.43, 95% CI = −7.03 to 4.16), physical functioning (least-squares mean difference = −1.05, 95% CI = −6.59 to 4.50), or EuroQol 5-Dimension questionnaire visual analog scale (least-squares mean difference = 0.18, 95% CI = −5.04 to 5.39) and no between-group difference in time to deterioration in QLQ-C30 global health status/QOL, emotional functioning, or physical functioning. Conclusions Together with the efficacy and safety findings, patient-reported outcome results from KEYNOTE-355 support pembrolizumab plus chemotherapy as a standard of care for patients with advanced triple-negative breast cancer with tumor PD-L1 expression (combined positive score ≥10). [ABSTRACT FROM AUTHOR]

Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating cerebrovascular dysfunction and inflammation following mild respiratory SARS-CoV-2 infection. To this end, we performed unbiased transcriptional analysis to identify brain endothelial cell signalling pathways dysregulated by mouse adapted SARS-CoV-2 MA10 in aged immunocompetent C57Bl/6 mice in vivo. This analysis revealed significant suppression of Wnt/β-catenin signalling, a critical regulator of blood–brain barrier (BBB) integrity. We therefore hypothesized that enhancing cerebrovascular Wnt/β-catenin activity would offer protection against BBB permeability, neuroinflammation, and neurological signs in acute infection. Indeed, we found that delivery of cerebrovascular-targeted, engineered Wnt7a ligands protected BBB integrity, reduced T-cell infiltration of the brain, and reduced microglial activation in SARS-CoV-2 infection. Importantly, this strategy also mitigated SARS-CoV-2 induced deficits in the novel object recognition assay for learning and memory and the pole descent task for bradykinesia. These observations suggest that enhancement of Wnt/β-catenin signalling or its downstream effectors could be potential interventional strategies for restoring cognitive health following viral infections. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are vital components of the innate immune system, serving as the first line of defense against pathogens by recognizing a wide array of molecular patterns. This review summarizes the critical roles of TLRs in immune surveillance and disease pathogenesis, focusing on their structure, signaling pathways, and implications in various disorders. We discuss the molecular intricacies of TLRs, including their ligand specificity, signaling cascades, and the functional consequences of their activation. The involvement of TLRs in infectious diseases, autoimmunity, chronic inflammation, and cancer is explored, highlighting their potential as therapeutic targets. We also examine recent advancements in TLR research, such as the development of specific agonists and antagonists, and their application in immunotherapy and vaccine development. Furthermore, we address the challenges and controversies surrounding TLR research and outline future directions, including the integration of computational modeling and personalized medicine approaches. In conclusion, TLRs represent a promising frontier in medical research, with the potential to significantly impact the development of novel therapeutic strategies for a wide range of diseases. [ABSTRACT FROM AUTHOR]

The search for melatonin receptor agonists formed the main part of melatonin medicinal chemistry programs for the last three decades. In this short review, we summarize the two main aspects of these programs: the development of all the necessary tools to characterize the newly synthesized ligands at the two melatonin receptors MT1 and MT2, and the medicinal chemist's approaches to find chemically diverse ligands at these receptors. Both strategies are described. It turns out that the main source of tools were industrial laboratories, while the medicinal chemistry was mainly carried out in academia. Such complete accounts are interesting, as they delineate the spirits in which the teams were working demonstrating their strength and innovative character. Most of the programs were focused on nonselective agonists and few of them reached the market. In contrast, discovery of MT1‐selective agonists and melatonergic antagonists with proven in vivo activity and MT1 or MT2‐selectivity is still in its infancy, despite the considerable interest that subtype selective compounds may bring in the domain, as the physiological respective roles of the two subtypes of melatonin receptors, is still poorly understood. Poly‐pharmacology applications and multitarget ligands have also been considered. [ABSTRACT FROM AUTHOR]

As one of the peroxisome-proliferator-activated receptors (PPARs) members, PPARγ is a ligand binding and activated nuclear hormone receptor, which is an important regulator in metabolism, proliferation, tumor progression, and immune response. Increased evidence suggests that activation of PPARγ in response to ligands inhibits multiple types of cancer proliferation, metastasis, and tumor growth and induces cell apoptosis including breast cancer, colon cancer, lung cancer, and bladder cancer. Conversely, some reports suggest that activation of PPARγ is associated with tumor growth. In addition to regulating tumor progression, PPARγ could promote or inhibit tumor immunotherapy by affecting macrophage differentiation or T cell activity. These controversial findings may be derived from cancer cell types, conditions, and ligands, since some ligands are independent of PPARγ activity. Therefore, this review discussed the dual role of PPARγ on tumor progression and immunotherapy. [ABSTRACT FROM AUTHOR]

Model correlation of solubilities of task-specific ligands in supercritical carbon dioxide medium (SC-CO2) plays an important role in development of green separation methods for recovery of metal ions. In the present study, a new semi-empirical model was proposed to predict the solubility of ligands in SC-CO2 medium and is a modified version of existing Chrastil model. The correlation ability of new model was compared with existing density-based models (Chrastil, Adachi–Lu, del Valle–Aguilera, Sparks, Sung–Shim, Mendez-Santiago–Teja, and Bartle). New model evaluation studies were carried out using reported solubility data of 31 metal ion-specific ligands. The prediction ability of new model was compared using different objective functions, coefficient of determination (R2), absolute average relative deviation (AARD), and Akaike information criteria. The proposed model is accurate for correlating the solubility of ligands with a global AARD of 8.47%. The model was found to be most suitable for predicting the solubility of organophosphorus ligands with a mean AARD of 4.67%. Therefore, the proposed model can be employed for successful prediction of solubility of ligands in SC-CO2 medium. [ABSTRACT FROM AUTHOR]

Ligand density control strategy enhances the excitons dissociation and interparticle energy transfer, achieving efficient CO 2 photocatalytic conversion on CsPbBr 3 perovskite quantum dot. [Display omitted] Perovskite quantum dots (PQDs) hold immense potential as photocatalysts for CO 2 reduction due to their remarkable quantum properties, which facilitates the generation of multiple excitons, providing the necessary high-energy electrons for CO 2 photoreduction. However, harnessing multi-excitons in PQDs for superior photocatalysis remains challenging, as achieving the concurrent dissociation of excitons and interparticle energy transfer proves elusive. This study introduces a ligand density-controlled strategy to enhance both exciton dissociation and interparticle energy transfer in CsPbBr 3 PQDs. Optimized CsPbBr 3 PQDs with the regulated ligand density exhibit efficient photocatalytic conversion of CO 2 to CO, achieving a 2.26-fold improvement over unoptimized counterparts while maintaining chemical integrity. Multiple analytical techniques, including Kelvin probe force microscopy, temperature-dependent photoluminescence, femtosecond transient absorption spectroscopy, and density functional theory calculations, collectively affirm that the proper ligand termination promotes the charge separation and the interparticle transfer through ligand-mediated interfacial electron coupling and electronic interactions. This work reveals ligand density-dependent variations in the gas-solid photocatalytic CO 2 reduction performance of CsPbBr 3 PQDs, underscoring the importance of ligand engineering for enhancing quantum dot photocatalysis. [ABSTRACT FROM AUTHOR]

This article, published in the journal Synlett, examines the regioselectivity of metal-catalyzed aryne reactions. Arynes are reactive compounds used to synthesize valuable species, but these reactions often result in mixtures of regioisomeric products. The article discusses the regioselectivity of free arynes and the use of electronically influencing groups to induce regioselectivity. It also explores the lack of a regioselectivity model for metal-bound arynes and the potential for ligands to control regioselectivity in aryne transformations. The authors conducted experiments using different ligands and aryne precursors to determine their impact on regioselectivity, finding that factors such as ligand size, electron donation, and steric encumbrance of the aryne influence regioselectivity. The study demonstrates the potential of ligand control in inducing regioselectivity and provides insights into the factors governing metallated aryne selectivity. [Extracted from the article]

Advancing the synthesis of HfO2 nanocrystals, a refined anhydrous protocol that enables kinetic trapping of the metastable tetragonal phase and modulates twinning defects in anisotropically grown monoclinic nanoprisms is presented. This evolved sol–gel approach examines the role of the capping agent tri‐n‐octylphosphine oxide (TOPO) and introduces a novel heating strategy with sequential growth stages. Replacement of TOPO with triphenylphosphine oxide (TPPO) leads to the formation of prismatic hafnia nanocrystals exhibiting pristine {011}‐facets of the monoclinic phase. Furthermore, a hot‐injection inspired heating approach yields sub‐4 nm isotropic HfO2 nanocrystals in the tetragonal phase, bypassing the need for aliovalent cation species. In contrast, a heat‐up approach culminates in the generation of well‐characterized HfO2 nanorods. With sophisticated transmission electron microscopy analysis and the Wulff construction method, insights into the structural nucleation of nanoparticle growth are provided. This synthesis offers exceptional control and facilitates the formation of self‐assemblies akin to liquid crystals, opening the door for new applications with nanocolloidal HfO2. [ABSTRACT FROM AUTHOR]

Three mono(arylhydrazino)acenaphthenones, that is, mono(2-pyridylhydrazino)acenaphthenone (Py-mhan, L1), mono(4-cyanophenylhydrazino)acenaphthenone (4-CN-Ph-mhan, L2), and mono(3,4,6-trifluoro-2-pyridylhydrazino)acenaphthenone (FPy-mhan, L3), were synthesized by the reaction of acenaphthene quinone with the appropriate arylhydrazine salt; compounds L2 and L3 were obtained for the first time. The subsequent reaction of L1 with nickel chloride in 2 : 1 ratio led to the octahedral complex [Ni(Py-mhan)2] (I), in which Py-mhan acts as a tridentate ligand. All of the prepared compounds were characterized by elemental analysis, IR and 1H NMR spectroscopy, and cyclic voltammetry; the crystal structures of L3 and I were determined by X-ray diffraction. [ABSTRACT FROM AUTHOR]

Dual photoredox catalysis has revolutionized the field of cross‐coupling reactions, enabling the discovery of numerous highly efficient reactions. This breakthrough is attributed to the exceptional combination of nickel catalysis with photoredox catalysis. Nickel exhibits both oxidative addition and reductive elimination processes, and a wide range of oxidation states (ranging from I to IV) accessible within a single catalytic cycle. Furthermore, nickel complexes are capable of catalyzing various processes through radical mechanisms. The latest feature has proven to be incredibly potent in facilitating the formation of new C−C and C−X bonds (X=H, O, S, N). The powerful combination of photoredox and nickel catalysis reveals an expansive domain of unexplored possibilities. It offers unparalleled opportunities for improving reactions and exploring innovative pathways. Under photoredox conditions, it is possible to form nucleophilic reactive organometallic intermediates, useful in reaction with electrophiles. We have devoted a research program towards the rediscovery and use of organometallic reagents, introduced by Corey, Hegedus, and Semmelack many years ago. The results unveiled the extraordinary capabilities of photoredox catalysis, enabling the creation and efficient utilization of potent nucleophilic organometallic reagents under mild conditions, free from the need for strong bases or stoichiometric metal reductants. [ABSTRACT FROM AUTHOR]

Ultra‐high field (UHF) magnetic resonance imaging (MRI) has emerged as a focal point of interest in the field of cancer diagnosis. Despite the ability of current paramagnetic or superparamagnetic smart MRI contrast agents to selectively enhance tumor signals in low‐field MRI, their effectiveness at UHF remains inadequate due to inherent magnetism. Here, we report a ligand‐mediated magnetism‐conversion nanoprobe (MCNP) composed of 3‐mercaptopropionic acid ligand‐coated silver‐gadolinium bimetallic nanoparticles. The MCNP exhibits a pH‐dependent magnetism conversion from ferromagnetism to diamagnetism, facilitating tunable nanomagnetism for pH‐activatable UHF MRI. Under neutral pH, the thiolate (−S−) ligands lead to short τ′m and increased magnetization of the MCNPs. Conversely, in the acidic tumor microenvironment, the thiolate ligands are protonated and transform into thiol (−SH) ligands, resulting in prolonged τ′m and decreased magnetization of the MCNP, thereby enhancing longitudinal relaxivity (r1) values at UHF MRI. Notably, under a 9 T MRI field, the pH‐sensitive changes in Ag−S binding affinity of the MCNP lead to a remarkable (>10‐fold) r1 increase in an acidic medium (pH 5.0). In vivo studies demonstrate the capability of MCNPs to amplify MRI signal of hepatic tumors, suggesting their potential as a next‐generation UHF‐tailored smart MRI contrast agent. [ABSTRACT FROM AUTHOR]

Asymmetric hydrogenation finds widespread application in academia and industry. And indeed, a number of processes have been implemented for the production of pharma and agro intermediates as well as flavors & fragrances. Although these processes are all based on the use of late transition metals as catalysts, there is an increasing interest in the use of base metal catalysis in view of their lower cost and the expected different substrate scope. Catalysts based on cobalt have already shown their potential in enantioselective hydrogenation chemistry. This review outlines the impressive progress made in recent years on cobalt‐catalyzed asymmetric hydrogenation of different unsaturated substrates. We also illustrate the ligand dependent substrate specificity as well as the mechanistic variability in detail. This may well guide further catalyst development in this research area. [ABSTRACT FROM AUTHOR]

That signaling bias is a nth level of complexity in the understanding of G protein-coupled receptor (GPCR) activation is a first fact. That its exhaustive description, including the mode d'emploi of its quantitative measurement, remains a challenge is a second fact. That the use of this concept is promising for the design of drug candidates is a third fact. That the translation of signaling biases observed into in vivo specific effects is well documented is a fourth fact. However, the road to apply those aspects of receptology to a systematic description of a ligand and, a fortiori, of a drug candidate, still necessitates a huge body of studies. In the present commentary, the merits of the molecular description of receptor bias signaling are highlighted and the ligand induced-fit impact on GPCR structure, as well as on the functional repertoire of GPCRs, is discussed. An emphasis is given to the practical aspects during drug design, and, thus, the practical limitations of the current approaches, particularly in the context of as soon as the data are transferred to more integrated/living systems, might be a major limitation. [ABSTRACT FROM AUTHOR]