Potential Applications In Drug Discovery Research Articles

Streamlined Electrochemical Dihalogenation (F, Cl, and Br) of gem‐Difluoroalkenes Using Hydrogen Halides as Reagents

AbstractWe established a straightforward electrochemical dihalogenation (F, Cl, and Br) process for gem‐difluoroalkenes. This reaction exhibits a broad functional group tolerance and has been effectively utilized in the construction of complex molecules. The subsequent synthetic transformations of the products have highlighted the adaptable nature of the dihalogenated compounds, demonstrating their potential application in drug discovery and the investigation of innovative materials. The effective utilization of the dihalogenated product for 18F‐labeling represents a novel approach in generating highly potent 18F‐labeled tracers.

Overcoming Challenges in O-Nitration: Selective Alcohol Nitration Deploying N,6-Dinitrosaccharin and Lewis Acid Catalysis.

Nitrate esters hold pivotal roles in pharmaceuticals, energetic materials, and atmospheric processes, motivating the development of efficient synthesis routes. Here, we present a novel catalytic method for the synthesis of nitrates via the direct O-nitration of alcohols, addressing limitations of current traditional methods. Leveraging bench-stable and recoverable N,6-dinitrosaccharin reagent, our catalytic strategy employs magnesium triflate to achieve mild and selective O-nitration of alcohols, offering broad substrate scope and unprecedented large functional group tolerance (e.g. alkenes, alkynes, carbonyls). DFT mechanistic studies reveal a dual role of the magnesium catalyst in the activation of both the nitrating reagent and the alcohol substrate. They also unveil a barrierless proton transfer upon formation of a widely-accepted - yet elusive in solution - nitrooxonium ion intermediate. Overall, our work contributes to the development of mild, selective, and sustainable approaches to nitrates synthesis, with potential applications in drug discovery, materials science, and environmental chemistry.

Overcoming Challenges in O‐Nitration: Selective Alcohol Nitration Deploying N,6‐Dinitrosaccharin and Lewis Acid Catalysis

Nitrate esters hold pivotal roles in pharmaceuticals, energetic materials, and atmospheric processes, motivating the development of efficient synthesis routes. Here, we present a novel catalytic method for the synthesis of nitrates via the direct O‐nitration of alcohols, addressing limitations of current traditional methods. Leveraging bench‐stable and recoverable N,6‐dinitrosaccharin reagent, our catalytic strategy employs magnesium triflate to achieve mild and selective O‐nitration of alcohols, offering broad substrate scope and unprecedented large functional group tolerance (e.g. alkenes, alkynes, carbonyls). DFT mechanistic studies reveal a dual role of the magnesium catalyst in the activation of both the nitrating reagent and the alcohol substrate. They also unveil a barrierless proton transfer upon formation of a widely‐accepted — yet elusive in solution — nitrooxonium ion intermediate. Overall, our work contributes to the development of mild, selective, and sustainable approaches to nitrates synthesis, with potential applications in drug discovery, materials science, and environmental chemistry.

Highlights on Fluorine-containing Drugs Approved by U.S. FDA in 2023.

Fluorine continues to show its potential applications in drug discovery and development, as reflected by twelve drugs being fluorinated out of the fifty-five approved by the FDA in 2023. This concise review highlights the discovery of each of these fluorine-containing drugs in the past year, including its brand name, date of approval, composition, sponsors, indication, and mechanism of action. The relevant future trend is also briefly discussed.

Direct Construction of C-Alkyl Glycosides from Non-Activated Olefins via Nickel-Catalyzed C(sp3)─C(sp3) Coupling Reaction.

Among C-glycosides, C-alkyl glycosides are significant building blocks for natural products and glycopeptides. However, research on efficient construction methods for C-alkyl glycosides remains relatively limited. Compared with Michael acceptors, non-activated olefins are more challenging substrates and have rarely been employed in the construction of C-glycosides. Here, a highly efficient and convenient approach for the synthesis of C-alkyl glycosides through a nickel-catalyzed C(sp3)-C(sp3) coupling reaction is presented. A distinctive feature of this method is its utilization of non-activated olefins as the anomeric radical acceptors for hydroalkylation, allowing for the direct formation of C-glycoside bonds in a single step. Furthermore, this method demonstrates excellent compatibility with a broad scope of highly reactive functional groups. Mechanistic investigations suggest that the reaction proceeds via a free radical pathway, leading predominantly to the formation of products with α-configuration. Overall, this innovative methodology offers a versatile and practical approach for the synthesis of C-alkyl glycosides, offering new avenues for the production of intricate glycosides with potential applications in drug discovery and chemical biology.

An Experimental and Computational Approach to The Microwave‐Assisted Synthesis of 2’‐Hydoxychalcone Derivatives in 1‐Dodecyl‐3‐Methylimidazolium Bromide ([DDMIm]Br) Ionic Liquids

AbstractFour derivatives of 2’‐hydoxychalcone were synthesized through Claisen‐Schmidt condensation by combining 2’‐hydroxyacetophenone and four different benzaldehyde derivatives (o‐vanillin, salicylaldehyde, p‐anisaldehyde, and benzaldehyde) in the presence of a base. The reactions took place in an ionic liquid, 1‐dodecyl‐3‐methylimidazolium bromide ([DDMIm]Br), and were facilitated by microwave irradiation. The reactions were completed within 10 to 15 minutes, yielding products with chemical yields ranging from 52.64 % to 83.42 %. The structures of the synthesized products were confirmed using 1H NMR and 13C NMR spectroscopy. Additionally, antimicrobial activity tests demonstrated the effectiveness of specific derivatives against Staphylococcus aureus and Escherichia coli, underscoring the importance of hydroxy and methoxy groups on the aromatic ring in inhibiting microbial growth. These findings provide valuable knowledge for developing chalcone derivatives with improved properties and potential applications in drug discovery. Furthermore, the synthesized products′ reactivity was analyzed using Frontier Molecular Orbital (FMO) and their reactivity site was mapped using Molecular Electrostatic Potential (MEP). Lastly, molecular docking analysis was attempted to explain antibacterial activities from all products. Nonetheless, the molecular docking simulations conducted in this study were inadequate to fully account for the antimicrobial activity observed in all the products.

Harnessing the power of seaweed: unveiling the potential of marine algae in drug discovery

Seaweeds, also known as marine algae, have gained attention as a promising source of bioactive compounds with potential applications in drug discovery. This review explores the emerging field of seaweed-based drug discovery and highlights the diverse range of bioactive compounds found in seaweeds, including polysaccharides, phlorotannins, pigments, and peptides. These compounds exhibit various pharmacological activities such as antioxidant, anti-inflammatory, antimicrobial, antiviral, and anticancer effects. Seaweeds have demonstrated particular promise in the areas of cancer research, with certain species showing potent antitumor properties. Additionally, their anti-inflammatory, antimicrobial, and neuroprotective potential has captured scientific interest in the treatment of chronic diseases and neurodegenerative disorders. However, challenges related to compound identification, extraction methods, scalability of seaweed cultivation, and understanding the mechanisms of action still need to be addressed. As researchers employ advanced technologies and dive deeper into the chemical composition of seaweeds, the untapped potential of these marine organisms in drug discovery awaits further exploration and holds significant promise for future therapeutic advancements.

Dark kinase annotation, mining, and visualization using the Protein Kinase Ontology

The Protein Kinase Ontology (ProKinO) is an integrated knowledge graph that conceptualizes the complex relationships among protein kinase sequence, structure, function, and disease in a human and machine-readable format. In this study, we have significantly expanded ProKinO by incorporating additional data on expression patterns and drug interactions. Furthermore, we have developed a completely new browser from the ground up to render the knowledge graph visible and interactive on the web. We have enriched ProKinO with new classes and relationships that capture information on kinase ligand binding sites, expression patterns, and functional features. These additions extend ProKinO’s capabilities as a discovery tool, enabling it to uncover novel insights about understudied members of the protein kinase family. We next demonstrate the application of ProKinO. Specifically, through graph mining and aggregate SPARQL queries, we identify the p21-activated protein kinase 5 (PAK5) as one of the most frequently mutated dark kinases in human cancers with abnormal expression in multiple cancers, including a previously unappreciated role in acute myeloid leukemia. We have identified recurrent oncogenic mutations in the PAK5 activation loop predicted to alter substrate binding and phosphorylation. Additionally, we have identified common ligand/drug binding residues in PAK family kinases, underscoring ProKinO’s potential application in drug discovery. The updated ontology browser and the addition of a web component, ProtVista, which enables interactive mining of kinase sequence annotations in 3D structures and Alphafold models, provide a valuable resource for the signaling community. The updated ProKinO database is accessible at https://prokino.uga.edu.

How to More Effectively Obtain Ginsenoside Rg5: Understanding Pathways of Conversion.

Ginsenoside Rg5, a relatively uncommon secondary ginsenoside, exhibits notable pharmacological activity and is commonly hypothesized to originate from the dehydration of Rg3. In this work, we compared different conversion pathways using Rb1, R-Rg3 and S-Rg3 as the raw material under simple acid catalysis. Interestingly, the results indicate that the conversion follows this reaction activity order Rb1 > S-Rg3 > R-Rg3, which is contrary to the common understanding of Rg5 obtained from Rg3 by dehydration. Our experimental results have been fully confirmed by theoretical calculations and a NOESY analysis. The DFT analysis reveals that the free energies of S-Rg3 and R-Rg3 in generating carbocation are 7.56 mol/L and 7.57 mol/L, respectively, which are significantly higher than the free energy of 1.81 mol/L when Rb1 generates the same carbocation. This finding aligns with experimental evidence suggesting that Rb1 is more prone to generating Rg5 than Rg3. The findings from the nuclear magnetic resonance (NMR) analysis suggest that the fatty chains (C22-C27) in R-Rg3 and S-Rg3 adopt a Gauche conformation and an anti conformation with C16-C17 and C13-C17, respectively, due to the relatively weak repulsive van der Waals force. Therefore, the configuration of R-Rg3 is more conducive to the formation of intramolecular hydrogen bonds between 20C-OH and 12C-OH, whereas S-Rg3 lacks this capability. Consequently, this also explains the fact that S-Rg3 is more prone to dehydration to generate Rg5 than R-Rg3. Additionally, our research reveals that the synthetic route of Rg5 derived from protopanaxadiol (PPD)-type ginsenosides (including Rb1, Rb2, Rb3, Rc and Rd) exhibits notable advantages in terms of efficacy, purity and yield when compared to the pathway originating from Rg3. Moreover, this study presents a highly effective and practical approach for the extensive synthesis of Rg5, thereby facilitating the exploration of its pharmacological properties and potential application in drug discovery.

Network pharmacology‒based analysis of marine cyanobacteria derived bioactive compounds for application to Alzheimer's disease.

In recent years, the Alzheimer's disease (AD) epidemic has become one of the largest global healthcare crises. Besides, the available systemic therapies for AD are still inadequate. Due to the insufficient therapeutic options, new treatment strategies are urgently needed to achieve a satisfactory therapeutic effect. Marine bio-resources have been accepted as one of the most economically viable and sustainable sources with potential applications for drug discovery and development. In this study, a marine cyanobacteria-Synechococcus sp. XM-24 was selected as the object of research, to systematically investigate its therapeutic potential mechanisms for AD. The major active compounds derived from the Synechococcus sp. biomass were identified via pyrolysis-gas chromatography-mass spectrometry (GC-MS), and 22 compounds were identified in this strain. The most abundant chemical compounds was (E)-octadec-11-enoic acid, with the peak area of 30.6%. Follow by tridecanoic acid, 12-methyl- and hexadecanoic acid, with a peak area of 23.26% and 18.23%, respectively. GC-MS analysis also identified indolizine, isoquinoline, 3,4-dihydro- and Phthalazine, 1-methyl-, as well as alkene and alkane from the strain. After the chemical toxicity test, 10 compounds were finally collected to do the further analysis. Then, network pharmacology and molecular docking were adopted to systematically study the potential anti-AD mechanism of these compounds. Based on the analysis, the 10 Synechococcus-derived active compounds could interact with 128 related anti-AD targets. Among them, epidermal growth factor receptor (EGFR), vascular endothelial growth factor A (VEGFA) and mitogen-activated protein kinase 3 (MAPK3) were the major targets. Furthermore, the compounds N-capric acid isopropyl ester, (E)-octadec-11-enoic acid, and 2H-Pyran-2,4(3H)-dione, dihydro-6-methyl- obtained higher degrees in the compounds-intersection targets network analysis, indicating these compounds may play more important role in the process of anti-AD. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that these active compounds exert the anti-AD effects mainly through PI3K-Akt signaling pathway, neuroactive ligand-receptor interaction and ras signaling pathway. Our study identified Synechococcus-derived bioactive compounds have the potential for application to AD by targeting multiple targets and related pathways, which will provide a foundation for future research on applications of marine cyanobacteria in the functional drug industry.

GeoDILI: A Robust and Interpretable Model for Drug-Induced Liver Injury Prediction Using Graph Neural Network-Based Molecular Geometric Representation.

Drug-induced liver injury (DILI) is a significant cause of drug failure and withdrawal due to liver damage. Accurate prediction of hepatotoxic compounds is crucial for safe drug development. Several DILI prediction models have been published, but they are built on different data sets, making it difficult to compare model performance. Moreover, most existing models are based on molecular fingerprints or descriptors, neglecting molecular geometric properties and lacking interpretability. To address these limitations, we developed GeoDILI, an interpretable graph neural network that uses a molecular geometric representation. First, we utilized a geometry-based pretrained molecular representation and optimized it on the DILI data set to improve predictive performance. Second, we leveraged gradient information to obtain high-precision atomic-level weights and deduce the dominant substructure. We benchmarked GeoDILI against recently published DILI prediction models, as well as popular GNN models and fingerprint-based machine learning models using the same data set, showing superior predictive performance of our proposed model. We applied the interpretable method in the DILI data set and derived seven precise and mechanistically elucidated structural alerts. Overall, GeoDILI provides a promising approach for accurate and interpretable DILI prediction with potential applications in drug discovery and safety assessment. The data and source code are available at GitHub repository (https://github.com/CSU-QJY/GeoDILI).

Knowledge Graphs and Their Applications in Drug Discovery.

Knowledge graphs represent information in the form of entities and relationships between those entities. Such a representation has multiple potential applications in drug discovery, including democratizing access to biomedical data, contextualizing or visualizing that data, and generating novel insights through the application of machine learning approaches. Knowledge graphs put data into context and therefore offer the opportunity to generate explainable predictions, which is a key topic in contemporary artificial intelligence. In this chapter, we outline some of the factors that need to be considered when constructing biomedical knowledge graphs, examine recent advances in mining such systems to gain insights for drug discovery, and identify potential future areas for further development.

Visible-Light-Induced Three-Component Tetrafluoroethyl-heteroarylation of Alkenes with 1,1,2,2-Tetrafluoroethanesulfonyl Chloride and Quinoxalin-2(1H)-ones.

1,1,2,2-Tetrafluoroethyl-containing compounds are valuable structures due to their unique physicochemical properties, which have increasing potential application in drug discovery. However, synthetic methods for preparing such compounds are rare. Herein, we report the first use of 1,1,2,2-tetrafluoroethanesulfonyl chloride to introduce the HCF2 CF2 group into organic molecules via a three-component, radical tetrafluoroethyl-heteroarylation of alkenes with readily available quinoxalin-2(1H)-ones. This method provides a new and facile approach for late-stage functionalization of potential biologically active molecules.

Dynamic Kinetic Resolution of Indole-Based Sulfenylated Heterobiaryls by Rhodium-Catalyzed Atroposelective Reductive Aldol Reaction.

A highly enantio- and diastereoselective dynamic kinetic resolution (DKR) of configurationally labile 3-aryl indole-2-carbaldehydes is described. The DKR proceeds via a Rh-catalyzed intermolecular asymmetric reductive aldol reaction with acrylate esters, with simultaneous generation of three stereogenic elements. The strategy relies on the labilization of the stereogenic axis that takes place thanks to a transient Lewis acid-base interaction (LABI) between the formyl group and a thioether moiety strategically located at the ortho' position. The atropisomeric indole products present a high degree of functionalization and can be further converted to a series of axially chiral derivatives, thereby expanding their potential application in drug discovery and asymmetric catalysis.

Glucosyl hesperidin exhibits more potent anxiolytic activity than hesperidin accompanied by the attenuation of noradrenaline induction in a zebrafish model.

Anxiety is a symptom of various mental disorders, including depression. Severe anxiety can significantly affect the quality of life. Hesperidin (Hes), a flavonoid found in the peel of citrus fruits, reportedly has various functional properties, one of which is its ability to relieve acute and chronic stress. However, Hes is insoluble in water, resulting in a low absorption rate in the body and low bioavailability. Glucosyl hesperidin (GHes) is produced by adding one glucose molecule to hesperidin. Its water solubility is significantly higher than that of Hes, which is expected to improve its absorption into the body and enhance its effects. However, its efficacy in alleviating anxiety has not yet been investigated. Therefore, in this study, the anxiolytic effects of GHes were examined in a zebrafish model of anxiety. Long-term administration of diets supplemented with GHes did not cause any toxicity in the zebrafish. In the novel tank test, zebrafish in the control condition exhibited an anxious behavior called freezing, which was significantly suppressed in GHes-fed zebrafish. In the black-white preference test, which also induces visual stress, GHes-fed zebrafish showed significantly increased swimming time in the white side area. Furthermore, in tactile (low water-level stress) and olfactory-mediated stress (alarm substance administration test) tests, GHes suppressed anxious behavior, and these effects were stronger than those of Hes. Increased noradrenaline levels in the brain generally cause freezing; however, in zebrafish treated with GHes, the amount of noradrenaline after stress was lower than that in the control group. Activation of c-fos/ERK/Th, which is upstream of the noradrenaline synthesis pathway, was also suppressed, while activation of the CREB/BDNF system, which is vital for neuroprotective effects, was significantly increased. These results indicate that GHes has a more potent anxiolytic effect than Hes in vivo, which may have potential applications in drug discovery and functional food development.

NGS Analysis to Detect Mutation in Brain Tumor Diagnostic

Abstract: This study presents an integrated computational approach for analyzing protein sequences and their 3D structures. By leveraging the MMDB Macromolecular database, homologs of a protein sequence of interest are identified, and interactive visualization of their structural properties is provided. The computational alignment method, using BLASTP, allows for efficient determination of sequence similarities and identification of conserved regions among multiple protein sequences. COBALT is employed to refine sequence alignments and facilitate graphical analysis of sequence relationships. RASMOL, a computational analysis program, generates 2-D representations of protein-ligand complexes, enabling visual exploration of their interactions. ORF finder is used to identify coding regions in mRNA sequences, aiding in the prediction of protein-coding regions. The approach is applied to brain tumor diagnostics using human biological samples, exploring the structural properties of brain tumor-related proteins with the help of the 2RHU protein structure and PYMOL visualization software. Overall, this integrated computational framework offers a comprehensive toolkit for protein sequence analysis, structure visualization, and homology modeling, with potential applications in drug discovery, molecular biology, and medical diagnostics

Atroposelective Access to Dihydropyridinones with C-N Axial and Point Chirality via NHC-Catalyzed [3 + 3] Annulation.

An N-heterocyclic carbene-catalyzed atroposelective [3 + 3] annulation of enals with 2-aminomaleate derivatives is described. A series of substituted dihydropyridones bearing both C-N axis and point chirality were synthesized with good diastereo- and enantioselectivity under mild conditions. This efficient strategy successfully superpositions an extra point chiral element with an axial backbone, and the generated structurally interesting atropisomers may have potential application in drug discovery.

On the Current Status of Ullmann-Type N-Arylation Reactions Promoted by Heterogeneous Catalysts

Ullmann-type C–N heterocoupling reactions have been applied for the syntheses of N-arylated amines. In the past decade, transition metal-catalyzed N-arylations have been recognized as particularly efficient procedures for the preparation of nitrogen-containing aromatic systems. These reactions typically carried out under optimized conditions, have also been found to be suitable for the synthesis of complex molecules with other functional groups, including natural products, drugs, or pharmaceuticals. Most importantly, copper-catalyzed N-arylations have been studied and employed in the total synthesis of biologically active compounds. The construction of fused N-heterocyclic compounds also remained the subject of extensive research because of their potential applications in drug discovery and the development of functional materials. The aim of this review is to summarize the recent progress in the synthetic applications of Ullmann-type N-arylation reactions performed in heterogeneous systems. In particular, the utilization of copper and palladium species immobilized on various support materials, modified by surface functionalization, has been discussed and evaluated.

Chromium-Catalyzed Defluorinative Reductive Coupling of Aldehydes with gem-Difluoroalkenes.

Herein, a mild and convenient defluorinative reductive cross coupling of gem-difluoroalkenes with aliphatic aldehydes has been developed to afford diverse silyl-protected β-fluorinated allylic alcohols. The reaction is operationally simple and shows good functional group tolerance with moderate to excellent yields. The utility of this method is demonstrated by converting the products into various bioactive fluorinated compounds, showing its potential applications in drug discovery and biochemistry.

Selective macrocyclic peptide modulators of Lys63-linked ubiquitin chains disrupt DNA damage repair

Developing an effective binder for a specific ubiquitin (Ub) chain is a promising approach for modulating various biological processes with potential applications in drug discovery. Here, we combine the Random Non-standard Peptides Integrated Discovery (RaPID) method and chemical protein synthesis to screen an extended library of macrocyclic peptides against synthetic Lys63-linked Di-Ub to discover a specific binder for this Ub chain. Furthermore, next-generation binders are generated by chemical modifications. We show that our potent cyclic peptide is cell-permeable, and inhibits DNA damage repair, leading to apoptotic cell death. Concordantly, a pulldown experiment with the biotinylated analog of our lead cyclic peptide supports our findings. Collectively, we establish a powerful strategy for selective inhibition of protein-protein interactions associated with Lys63-linked Di-Ub using cyclic peptides. This study offers an advancement in modulating central Ub pathways and provides opportunities in drug discovery areas associated with Ub signaling.