Search Results (250)

The discovery of a mechanism by which bile acids (BAs) regulate fat synthesis by modulating the activation of the farnesoid X receptor (FXR) in the liver and intestines has highlighted the central role of BAs in triglyceride synthesis in the liver. FXR has been reported as a promising drug target for primary biliary cholangitis, metabolic-dysfunction-associated steatohepatitis, and metabolic-dysfunction-associated steatotic liver disease. A large number of FXR modulators with various chemotypes have been developed by many research groups. Although several FXR modulators are advancing into clinical trials, ongoing efforts aim to develop new FXR modulators that minimize the adverse effects associated with long-term administration. To develop drug candidates targeting FXR, various heterocyclic and/or fused heteroaromatic rings have been employed as the core and/or parts of the structures, out of which benzimidazole has been recognized as a valuable structural motif due to its synthetic accessibility and its versatility in constructing structurally diverse target molecules. Herein, we report on the development of FXR modulators incorporating benzimidazole as a fused heteroaromatic ring. Full article

This study explores crude oil as a chemically and structurally heterogeneous system with potential pharmaceutical relevance beyond its established roles as an energy and feedstock resource. Recent advances in analytical technologies have enabled the detailed characterization of crude oil constituents at the molecular level, thereby linking structural features to physicochemical properties and possible biological activities. The presented analysis outlines the rationale, methodological considerations, and future research directions for integrating crude oil molecular motifs into the pharmaceutical chemical space. Beyond its conventional role as an industrial and energy resource, crude oil may also hold promise for drug discovery. This study seeks to provide a conceptual framework for reconsidering crude oil as a reservoir of pharmacologically relevant scaffolds and to outline methodological approaches for their systematic assessment. Its rigid sp³-rich frameworks, together with sterane/hopane biomarkers, porphyrins, and functional aromatics, structurally overlap with established therapeutic classes and are naturally present in crude oil in suitable abundance, offering opportunities to reduce synthetic effort and expand the chemical space accessible to drug discovery. Advances in petroleomics and in silico methodologies now enable petroleum-derived constituents to be characterized in terms of drug-likeness, bioactivity, and toxicity, providing a framework to reconsider crude oil as an unconventional but analytically and computationally tractable resource for pharmaceutical research. Full article

The indole scaffold represents a privileged structural motif in medicinal chemistry, celebrated for its remarkable chemical versatility, biological ubiquity, and clinical relevance. This review provides a comprehensive analysis of the recent research on the indole nucleus, emphasizing its physicochemical properties, reactivity patterns, and capacity to interact with a wide array of biological targets. Found in key endogenous compounds such as serotonin and melatonin, indole serves as a cornerstone in neurochemical signaling, circadian regulation, and chrono-metabolic homeostasis. Beyond its physiological roles, synthetic indole derivatives have shown extensive therapeutic potential across diverse domains, including oncology, infectious diseases, neurodegenerative disorders, immunomodulation, and metabolic syndromes. The review explores structure–activity relationships (SAR), pharmacokinetics, and the molecular mechanisms by which indole-based compounds exert their tremendous effects, that are ranging from enzyme inhibition to receptor modulation. Special focus is given to current clinical applications and emerging strategies for enhancing drug specificity, bioavailability, and safety through indolic frameworks. Additionally, we highlight the translational potential of indole-containing molecules in personalized medicine, underscoring opportunities for future drug discovery. By integrating insights from medicinal chemistry, biochemistry, pharmacology, and clinical science, this review affirms the indole ring’s enduring value as a central scaffold in therapeutic innovation. Full article

Peptide-based biomaterials have emerged as versatile tools for pharmaceutical drug delivery due to their biocompatibility and tunable sequences, yet a comprehensive overview of their categories, mechanisms, and optimization strategies remains lacking to guide clinical translation. This review systematically collates advances in peptide-based biomaterials, covering peptide excipients (cell penetrating peptides, tight junction modulating peptides, and peptide surfactants/stabilizers), self-assembling peptides (peptide-based nanospheres, cyclic peptide nanotubes, nanovesicles and micelles, peptide-based hydrogels and depots), and peptide linkers (for antibody drug-conjugates, peptide drug-conjugates, and prodrugs). We also dissect sequence-based optimization strategies, including rational design and biophysical optimization (cyclization, stapling, D-amino acid incorporation), functional motif integration, and combinatorial discovery with AI assistance, with examples spanning marketed drugs and research-stage candidates. The review reveals that cell-penetrating peptides enable efficient intracellular payload delivery via direct penetration or endocytosis; self-assembling peptides form diverse nanostructures for controlled release; and peptide linkers achieve site-specific drug release by responding to tumor-associated enzymes or pH cues, while sequence optimization enhances stability and targeting. Peptide-based biomaterials offer precise, biocompatible and tunable solutions for drug delivery, future advancements relying on AI-driven design and multi-functional modification will accelerate their transition from basic research to clinical application. Full article

The role of alternative nucleic acid structures (ANS) in biology is an area of increasing interest. These non-canonical structures include the Z-DNA and Z-RNA duplexes (ZNA), the three-stranded triplex, the four-stranded G-quadruplex (GQ), and i-motifs. Previously, the biological relevance of ANS was dismissed. Their formation in vitro often required non-physiological conditions, and there was no genetic evidence for their function. Further, structural studies confirmed that sequence-specific transcription factors (TFs) bound B-DNA. In contrast, ANS are formed dynamically by a subset of repeat sequences, called flipons. The flip requires energy, but not strand cleavage. Flipons are enriched in promoters where they modulate transcription. Here, computational modeling based on AlphaFold V3 (AF3), under optimized conditions, reveals that known B-DNA-binding TFs also dock to ANS, such as ZNA and GQ. The binding of HLH and bZIP homodimers to Z-DNA is promoted by methylarginine modifications. Heterodimers only bind preformed Z-DNA. The interactions of TFs with ANS likely enhance genome scanning to identify cognate B-DNA-binding sites in active genes. Docking of TF homodimers to Z-DNA potentially facilitates the assembly of heterodimers that dissociate and are stabilized by binding to a cognate B-DNA motif. The process enables rapid discovery of the optimal heterodimer combinations required to regulate a nearby promoter. Full article

A series of novel triazone derivatives containing acylhydrazone and phenoxypyridine motifs were designed, synthesized, and evaluated for their biological activities. The bioassay results indicated that most of the target compounds exhibited excellent insecticidal activities against bean aphids. In particular, compounds 3i and 3e showed excellent aphicidal activities comparable to pymetrozine, thus emerging as novel insecticidal lead compounds. Additionally, compounds 3c (60%), 3e (60%), and 3f (60%) exhibited good larvicidal activities against C. pipiens pallens at 0.5 mg/kg. Further fungicidal activity tests revealed that most derivatives exhibited broad-spectrum fungicidal activities. A total of twelve compounds exhibited better fungicidal activities against cercospora arachidicola hori than carbendazim, and eight compounds exhibited better fungicidal activities against fusarium moniliforme than carbendazim. This work suggests that compound 3e could serve as an insecticidal lead compound for further structural optimization. Full article

Cold-active lipolytic enzymes enable low-temperature biocatalysis, but remain underexplored in Antarctic actinomycetes. Here, we report the discovery and first-step characterization of a CALB-like cold-active lipolytic enzyme (PanLip) from Pseudonocardia antarctica. Sequence and structure analyses revealed a canonical α/β-hydrolase fold with a conserved Ser–Asp–His triad and short helical elements around the pocket reminiscent of CALB’s α5/α10 lid. Mature PanLip was expressed primarily as inclusion bodies in E. coli; an N-terminally truncation (PanLipΔN) improved solubility and PanLipΔN was purified by Ni–NTA. Far-UV CD confirmed a folded α/β architecture. PanLipΔN favored short-chain substrates (p-NPA, k_cat/K_M = 2.4 × 10⁵ M⁻¹·s⁻¹) but also showed measurable hydrolytic activity toward natural triglycerides, consistently with a lipase-family esterase. The enzyme showed an activity optimum near 25 °C and pH 8.0. The enzyme tolerated low salt (maximal at 0.1 M NaCl), mild glycerol, and selected organic solvents (notably n-hexane), but was inhibited by high salt, Triton X-100, and SDS. AlphaFold predicted high local confidence for the catalytic core; DALI placed PanLip closest to fungal lipases (AFLB/CALB). Temperature-series MD and CABS-flex indicated enhanced surface breathing and flexible segments adjacent to the active site—including a region topologically matching CALB α10—supporting a flexibility-assisted access mechanism at low temperature. Structure-based MSAs did not support a cold adaptation role for the reported VDLPGRS motif. Taken together, these findings position PanLip as a promising cold-active catalyst with CALB-like access control and potential for low-temperature biocatalysis. Full article

Copper transporter 1 (CTR1) is the primary high affinity importer for Cu(I) in eukaryotic cells. CTR1 plays an essential role in maintaining copper homeostasis which is crucial for diverse biological processes. Since its discovery in 1997, research on human CTR1 (hCTR1) has progressed from foundational biochemical characterization to detailed structural and functional elucidation, expanding our understanding of its involvement in human diseases. Here we summarize the current understanding of hCTR1, including its structural features, copper-binding motifs, regulation, trafficking pathways, and roles in disease. We also highlight emerging evidence implicating hCTR1 in cancer, neurodegenerative disorders, and inherited copper metabolism syndromes, emphasizing its potential as a therapeutic target and drug delivery facilitator. Finally, we discuss recent studies and outline future directions, aimed at fully harnessing the biomedical potential of hCTR1. Full article

One of the most important events in the pathogenesis of Parkinson’s disease and related disorders is the formation of abnormal fibrils via the aggregation of α-synuclein (α-syn) with β-sheet-rich organization. The use of Cryo-EM has uncovered different polymorphs of the fibrils, each having unique structural interfaces, which has made the design of inhibitors even more challenging. Here, a structure-guided framework incorporating AI-assisted peptide generation was set up with the objective of targeting the conserved β-sheet motifs that are present in various forms of α-syn fibrils. The ProteinMPNN, then, AlphaFold-Multimer, and PepMLM were employed to create short peptides that would interfere with the growth of the fibrils. The two selected candidates, T1 and S1, showed a significant inhibition of α-syn fibrillation, as measured by a decrease in the ThT fluorescence and the generation of either amorphous or fragmented aggregates. The inhibitory potency of the peptides was in line with the predicted interface energies. This research work illustrates that the integration of cryo-EM structural knowledge with the computational design method leads to the quick discovery of the wide-spectrum peptide inhibitors, which is a good strategy for the precision treatment of neurodegenerative diseases. Full article

Eukaryotic phosphorylation of serine and threonine residues is a central regulatory mechanism in cell signalling, carried out by more than 500 kinases and a diverse array of phosphatases. Traditionally understood as a two-component system driven by writers (kinases) and erasers (phosphatases), this regulatory network is now appreciated to involve additional proteins that modulate or interpret phosphorylation-dependent changes. Among them, the 14-3-3 protein family has emerged as a prominent example due to its ability to bind phosphorylated serine/threonine motifs—typically located within intrinsically disordered regions—and influence the activity, stability, or localization of its partners. In this review, we discuss the importance, evolution, structure, and dynamics of 14-3-3 proteins, as well as their interactions with small molecules—both natural and designed—that bind to them. We highlight several underexplored aspects of their molecular behaviour, integrate recent discoveries, and emphasize how these insights contribute to a broader understanding of phosphorylation-dependent regulation across eukaryotes. Full article

SH3 domains are widespread protein modules that mostly bind to proline-rich short linear motifs (SLiMs). Most known SH3 domain-motif interactions and canonical or non-canonical recognition specificities are described for individual SH3 domains. Although cooperation and coordinated motif binding between tandem SH3 domains has already been described for members of the p47^phox-related protein family, individual cases have never been collected and analyzed collectively, which precluded the definition of the binding preferences and targeted discovery of further instances. Here, we apply an integrative approach that includes data collection, curation, bioinformatics analyses and state-of-the-art structure prediction methods to fill these gaps. A search of the human proteome with the sequence signatures of SH3 tandemization and follow-up structure analyses suggest that SH3 tandemization could be specific for this family. We define the optimal binding preference of tandemly arranged SH3 domains as [PAVIL]PPR[PR][^DE][^DE] and propose potential new instances of this SLiM among the family members and their binding partners. Structure predictions suggest the possibility of a novel, reverse binding mode for certain motif instances. In all, our comprehensive analysis of this unique SH3 binding mode enabled the identification of novel, interesting tandem SH3-binding motif candidates with potential therapeutic relevance. Full article

Computational and machine learning approaches play a pivotal role in identifying, characterizing, and targeting noncanonical DNA structures, including G-quadruplexes, Z-DNA, hairpins, and triplexes. These configurations play critical roles in maintaining genomic stability, facilitating DNA repair, and regulating chromatin organization. Although the human genome predominantly adopts the B DNA conformation, evidence indicates that non-B DNA forms exert significant influence on gene expression and disease development. This highlights the need for dedicated computational frameworks to systematically investigate these alternative structures. Machine learning model, encompassing supervised and unsupervised algorithms such as K Nearest Neighbors, Support Vector Machines, and deep learning architectures including Convolutional Neural Networks, have shown considerable potential in predicting sequence motifs predisposed to forming non-B DNA conformations. These predictive tools contribute to identifying genomic regions associated with disease susceptibility. Complementary bioinformatics platforms and molecular docking tools, notably Auto Dock, along with chemical libraries like ZINC, facilitate the virtual screening of small molecules targeting specific DNA structures. Stabilizers of G quadruplexes, exemplified by CX 5461, have demonstrated therapeutic promise in BRCA-deficient cancers, highlighting the translational impact of computational methods on drug discovery. Anticipating DNA structural shifts opens new avenues in personalized medicine for complex diseases, with computational chemistry and machine learning deepening our understanding of DNA topology and guiding smarter ligand design. The integrated approach proposed in this review addresses the previous studies performed in this field and highlights the current limitations in structural genomics and advances the development of precision therapeutics aligned with individual genomic profiles. Full article

Nature has long served as a prolific source of bioactive compounds, offering structurally diverse scaffolds for the development of therapeutics. In recent years, increasing attention has been given to nature-inspired covalent inhibitors, molecules that form covalent bonds with pathogen- or cancer-specific targets, due to their potential selectivity and sustained biological activity. This review explores the landscape of covalent inhibitors derived from natural sources, with a focus on compounds from fungi, marine organisms, bacteria and plants. In particular, emphasis is placed on the molecular mechanisms through which these compounds exert their activity against different types of pathogens and other biomedically relevant targets, highlighting key structural motifs that facilitate covalent interactions. Furthermore, the review discusses recent advances in synthetic modification, target identification, and optimization strategies that bridge natural compound discovery with modern drug development. By drawing insights from nature’s chemical repertoire, this work ultimately displays the potential of natural covalent inhibitors as a promising foundation for next-generation anti-infective and anticancer therapeutics. Full article

Pulses and pseudocereals are sustainable protein sources of bioactive peptides (BAPs) with potential antioxidant, antihypertensive, antidiabetic, antimicrobial, and immunomodulatory activities. BAPs are typically liberated during gastrointestinal digestion or through bio-based processes, among which enzymatic hydrolysis and microbial fermentation represent the most widely applied strategies. Enzymatic hydrolysis provides controlled and reproducible release of short peptide motifs; recent advances such as ultrasound- or high-pressure–assisted hydrolysis enhance yield and bioactivity. Fermentation exploits microbial proteolytic activity to generate complex peptide mixtures, while improving sensory quality, reducing antinutritional compounds, and responding to consumer demand for natural and “clean-label” products. In silico tools increasingly complement these approaches by accelerating peptide discovery, predicting interactions with molecular targets, and guiding process design. This review provides an updated overview of bio-based methods to produce BAPs from pulses and pseudocereals, emphasizing the comparative advantages of enzymatic and fermentation technologies and their integration with computational tools. Moreover, it examines regulatory frameworks in the European Union, the United States, Japan, and China, while discussing current challenges for industrial scale-up and application in functional foods and nutraceuticals. These combined strategies offer a promising pathway to unlock the health and sustainability potential of plant proteins. Full article

Cellulose nanofibrils (CNFs) provide a green scaffold for next-generation flexible sensors. They unite abundance, mechanical robustness, biocompatibility, and an easily engineered surface. This review synthesizes advances from the past five years in low-carbon CNF manufacturing. We cover biomass pretreatment, high-solid mechanical fibrillation, and in situ functionalization. We then elucidate mechanisms that govern CNF films, aerogels, and double-network hydrogels used across humidity, temperature, strain/pressure, optical, electrochemical, and biosensing platforms. Particular attention is given to multiscale conductive networks, surface-charge regulation, and reversible dynamic crosslinking. Together, these motifs raise sensitivity, widen the linear response windows, and strengthen environmental tolerance. We interrogate bottlenecks that impede scale-up, including energy demand, batch-to-batch variability, and device-level integration. We also assess prospects for deep-eutectic-solvent recycling, roll-to-roll digital printing, and algorithm-guided structural design. Finally, we outline directions for self-healing and self-powered biomimetic architectures, fully degradable life-cycle design, and integrated “sense–store–compute” nodes. These analyses chart a credible path from laboratory discovery to industrial deployment of CNF-based sensing technologies. Full article