The infusions prepared from some Quercus L. species are used in folk medicine for medicinal purposes and consumed as tea. Quercus pontica K. Koch was selected in this study, for which no phytochemical isolation studies have been performed so far. Quercetin 3-O- β-D-glucopyranoside, kaempferol 3-O-(6\"\"-O-galloyl)-β-D-glucopyranoside, kaempferol 3-O-β-D-glucopyranoside, kaempferol 3-O-(6\"\'-coumaroyl-β-D-glucopyranoside, phlorizin, rosmarinic acid, and catechin were isolated from the titled plant for the first time. Some polyphenolic compounds have been shown to inhibit histone deacetylase (HDAC) enzymes. However, there is no study on the any activities of Quercus species in the literature. In this study, we demonstrated that the extract has in vitro pan-HDAC inhibition activity. Through a virtual screening study, the compounds were found to inhibit HDAC7 more strongly than the other HDAC isoforms; therefore, the HDAC7 inhibition activities were studied in vitro. Kaempferol 3-O-β-D-glucopyranoside and kaempferol 3-O-(6\'\"-coumaroyl-β-D-glucopyranoside) showed the best anti-HDAC7 activity with 37% and 41% inhibition at 500 μM.

Proanthocyanidins (OPACs) are the second largest class of plant metabolites after lignans. Although knowledge of their 3D conformations would add greatly to our understanding of their biological properties, very little has been published on the conformations of OPACs with a degree of polymerization (DP) above 4. We investigated the conformations of the linear epicatechin oligomers, prominent representatives of OPACs prevalent in apples and cocoa, where the epicatechin units are interconnected through the 4β-8 bonds. For DP-2 to DP-10 oligomers, conformational preferences reflected in the arrangement of consecutive flavan-3-ol units, are characterized by the φ torsion. For dimers, there are two energy wells corresponding to two preferred φ torsions, designated as compact and extended form. This behaviour is preserved in OPACs with higher DPs, but the most energetically favoured conformations are a combination of both, with compact-only or extended-only conformations being very unlikely. Thus, oligomers with DP ≥ 7 tend to assume an overall conformation approximating a spherical shape. This shape has a significant influence on the polarity of the OPAC oligomers expressed as 3D polar surface area, calculated using Spartan software for geometry-optimized 3D models, and possibly on other physicochemical properties. The results of polarity calculations provide a molecular-level rationale for the polarity-based chromatographic separation of the cocoa B-type procyanidins with DP range 4 to 10. In our experiments, using centrifugal partition chromatography (CPC) (a solvent system consisting of EtOAc-EtOH-water (6:1:5) v/v/v with aqueous phase stationary and upper phase mobile) we found that an enriched mixture of proanthocyanidins eluted first DP-1 (epicatechin) followed by consecutive elution of the DP-2 to DP-10 in the linear 4β-8 form. We demonstrated that such separation would not be possible if compact-only or extended-only conformations were present in solution. However, for the energy-favoured, spherically shaped conformations, the observed CPC elution order is fully justified.

The complexity of plant cell walls on different hierarchical levels still impedes the detailed understanding of biosynthetic pathways, interferes with processing in industry and finally limits applicability of cellulose materials. While there exist many challenges to readily accessing these hierarchies at (sub-) angström resolution, the development of advanced computational methods has the potential to unravel important questions in this field. Here, we summarize the contributions of molecular dynamics simulations in advancing the understanding of the physico-chemical properties of natural fibres. We aim to present a comprehensive view of the advancements and insights gained from molecular dynamics simulations in the field of carbohydrate polymers research. The review holds immense value as a vital reference for researchers seeking to undertake atomistic simulations of plant cell wall constituents. Its significance extends beyond the realm of molecular modeling and chemistry, as it offers a pathway to develop a more profound comprehension of plant cell wall chemistry, interactions, and behavior. By delving into these fundamental aspects, the review provides invaluable insights into future perspectives for exploration. Researchers within the molecular modeling and carbohydrates community can greatly benefit from this resource, enabling them to make significant strides in unraveling the intricacies of plant cell wall dynamics.

BACKGROUND: Cinnamomum tamala (Buch.-Ham.) T.Nees & Eberm., also known as Indian Bay leaf, holds a distinctive position in complementary and alternative medicinal systems due to its anti-inflammatory properties. However, the active constituents and key molecular targets by which C. tamala essential oil (CTEO) exerts its anti-inflammatory action remain unclear.
OBJECTIVE: The present study used network pharmacology and experimental validation to investigate the mechanism of CTEO in the treatment of inflammation.
METHODS: GC-MS analysis was used to identify the constituents of CTEO. The key constituents and core targets of CTEO against inflammation were obtained by network pharmacology. The binding mechanism between the active compounds and inflammatory genes was ascertained by molecular docking and molecular dynamics simulation analysis. The pharmacological mechanism predicted by network pharmacology was verified in lipopolysaccharide-stimulated murine macrophage (RAW 264.7) cell lines.
RESULTS: Forty-nine constituents were identified by GC-MS analysis, with 44 constituents being drug-like candidates. A total of 549 compounds and 213 inflammation-related genes were obtained, revealing 68 overlapping genes between them. Compound target network analysis revealed cinnamaldehyde as the core bioactive compound with the highest degree score. PPI network analysis demonstrated Il-1β, TNF-α, IL8, IL6 and TLR4 as key hub anti-inflammatory targets. KEGG enrichment analysis revealed a Toll-like receptor signalling pathway as the principally regulated pathway associated with inflammation. A molecular docking study showed that cinnamaldehyde strongly interacted with the Il-1β, TNF-α and TLR-4 proteins. Molecular dynamics simulations and MMPBSA analysis revealed that these complexes are stable without much deviation and have better free energy values. In cellular experiments, CTEO showed no cytotoxic effects on RAW 264.7 murine macrophages. The cells treated with LPS exhibited significant reductions in NO, PGE2, IL-6, TNF-α, and IL-1β levels following treatment with CTEO. Additionally, CTEO treatment reduced the ROS levels and increased the antioxidant enzymes such as SOD, GSH, GPx and CAT. Immunofluorescence analysis revealed that CTEO inhibited LPS-stimulated NF-κB nuclear translocation. The mRNA expression of TLR4, MyD88 and TRAF6 in the CTEO group decreased significantly compared to the LPS-treated group.
CONCLUSIONS: The current findings suggest that CTEO attenuates inflammation by regulating TLR4/MyD88/NF- κB signalling pathway.

An increasing number of drugs introduced to the market and numerous repositories of compounds with confirmed activity have posed the need to revalidate the state-of-the-art rules that determine the ranges of properties the compounds should possess to become future drugs. In this study, we designed a series of two chemotypes of aryl-piperazine hydantoin ligands of 5-HT7R, an attractive target in search for innovative CNS drugs, with higher molecular weight (close to or over 500). Consequently, 14 new compounds were synthesised and screened for their receptor activity accompanied by extensive docking studies to evaluate the observed structure-activity/properties relationships. The ADMET characterisation in terms of the biological membrane permeability, metabolic stability, hepatotoxicity, cardiotoxicity, and protein plasma binding of the obtained compounds was carried out in vitro. The outcome of these studies constituted the basis for the comprehensive challenge of computational tools for ADMET properties prediction. All the compounds possessed high affinity to the 5-HT7R (Ki below 250 nM for all analysed structures) with good selectivity over 5-HT6R and varying affinity towards 5-HT2AR, 5-HT1AR and D2R. For the best compounds of this study, the expression profile of genes associated with neurodegeneration, anti-oxidant response and anti-inflammatory function was determined, and the survival of the cells (SH-SY5Y as an in vitro model of Alzheimer\'s disease) was evaluated. One 5-HT7R agent (32) was characterised by a very promising ADMET profile, i.e. good membrane permeability, low hepatotoxicity and cardiotoxicity, and high metabolic stability with the simultaneous high rate of plasma protein binding and high selectivity over other GPCRs considered, together with satisfying gene expression profile modulations and neural cell survival. Such encouraging properties make it a good candidate for further testing and optimisation as a potential agent in the treatment of CNS-related disorders.

Every year, more than 19 million cancer cases are diagnosed, and this number continues to increase annually. Since standard treatment options have varying success rates for different types of cancer, understanding the biology of an individual\'s tumour becomes crucial, especially for cases that are difficult to treat. Personalised high-throughput profiling, using next-generation sequencing, allows for a comprehensive examination of biopsy specimens. Furthermore, the widespread use of this technology has generated a wealth of information on cancer-specific gene alterations. However, there exists a significant gap between identified alterations and their proven impact on protein function. Here, we present a bioinformatics pipeline that enables fast analysis of a missense mutation\'s effect on stability and function in known oncogenic proteins. This pipeline is coupled with a predictor that summarises the outputs of different tools used throughout the pipeline, providing a single probability score, achieving a balanced accuracy above 86%. The pipeline incorporates a virtual screening method to suggest potential FDA/EMA-approved drugs to be considered for treatment. We showcase three case studies to demonstrate the timely utility of this pipeline. To facilitate access and analysis of cancer-related mutations, we have packaged the pipeline as a web server, which is freely available at https://loschmidt.chemi.muni.cz/predictonco/ .Scientific contributionThis work presents a novel bioinformatics pipeline that integrates multiple computational tools to predict the effects of missense mutations on proteins of oncological interest. The pipeline uniquely combines fast protein modelling, stability prediction, and evolutionary analysis with virtual drug screening, while offering actionable insights for precision oncology. This comprehensive approach surpasses existing tools by automating the interpretation of mutations and suggesting potential treatments, thereby striving to bridge the gap between sequencing data and clinical application.

Organophosphates constitute a major class of pesticides widely employed in agriculture to manage insect pests. Their toxicity is attributed to their ability to inhibit the functioning of acetylcholinesterase (AChE), an essential enzyme for normal nerve transmission. Organophosphates, especially chlorpyrifos, have been a key component of the integrated pest management (IPM) in onions, effectively controlling onion maggot Delia antiqua, a severe pest of onions. However, the growing concerns over the use of this insecticide on human health and the environment compelled the need for an alternative organophosphate and a potential microbial agent for bioremediation to mitigate organophosphate pesticide pollution. In the present study, chloropyrifos along with five other organophosphate insecticides, phosmet, primiphos-methyl, isofenphos, iodofenphos and tribuphos, were screened against the target protein AChE of D. antiqua using molecular modeling and docking techniques. The results revealed that iodofenphos showed the best interaction, while tribuphos had the lowest interaction with the AChE based on comparative binding energy values. Further, protein-protein interaction analysis conducted using the STRING database and Cytoscap software revealed that AChE is linked with a network of 10 different proteins, suggesting that the function of AChE is disrupted through interaction with insecticides, potentially leading to disruption within the network of associated proteins. Additionally, an in silico study was conducted to predict the binding efficiency of two organophosphate degrading enzymes, organophosphohydrolase (OpdA) from Agrobacterium radiobacter and Trichoderma harzianum paraoxonase 1 like (ThPON1-like) protein from Trichoderma harzianum, with the selected insecticides. The analysis revealed their potential to degrade the pesticides, offering a promising alternative before going for cumbersome onsite remediation.

We previously reported on the interaction of 10-chloro-7H-benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one (10-Cl-BBQ) with the Aryl hydrocarbon Receptor (AhR) and selective growth inhibition in breast cancer cell lines. We now report on a library of BBQ analogues with substituents on the phenyl and naphthyl rings for biological screening. Herein, we show that absence of the phenyl Cl of 10-Cl-BBQ to produce the simple BBQ molecule substantially enhanced the growth inhibitory effect with GI50 values of 0.001-2.1 μM in select breast cancer cell lines MCF-7, T47D, ZR-75-1, SKBR3, MDA-MB-468, BT20, BT474 cells, while having modest effects of 2.1-7 μM in other cell lines including HT29, U87, SJ-G2, A2780, DU145, BE2-C, MIA, MDA-MB-231 or normal breast cells, MCF10A (3.2 μM). The most potent growth inhibitory effect of BBQ was observed in the triple negative cell line, MDA-MB-468 with a GI50 value of 0.001 μM, presenting a 3,200-fold greater response than in the normal MCF10A breast cells. Additions of Cl, CH3, CN to the phenyl ring and ring expansion from benzoimidazole to dihydroquinazoline hindered the growth inhibitory potency of the BBQ analogues by blocking potential sites of CYP1 oxidative metabolism, while addition of Cl or NO2 to the naphthyl rings restored potency. In a cell-based reporter assay all analogues induced 1.2 to 10-fold AhR transcription activation. Gene expression analysis confirmed the induction of CYP1 oxygenases by BBQ. The CYP1 inhibitor α-naphthoflavone, and the SULT1A1 inhibitor quercetin significantly reduced the growth inhibitory effect of BBQ, confirming the importance of both phase I and II metabolic activation for growth inhibition. Conventional molecular modelling/docking revealed no significant differences between the binding poses of the most and least active analogues. More detailed DFT analysis at the DSD-PBEP86/Def-TZVPP level of theory could not identify significant geometric or electronic changes which would account for this varied AhR activation. Generation of Fukui functions at the same level of theory showed that CYP1 metabolism will primarily occur at the phenyl head group of the analogues, and substituents within this ring lead to lower cytotoxicity.

The comprehension of molecular structure is pivotal in chemistry education. Over the past decade, Mahidol University International College has employed various teaching tools for the introductory chemistry laboratory class. This paper outlines our evolutionary shift from traditional tools, such as plastic and plasticine models, to the integration of computer software, and ultimately to augmented reality (AR) and virtual reality (VR) tools-specifically, MoleculARweb and MolecularWebXR developed by École Polytechnique Fédérale de Lausanne researchers. In this paper, we detail the implementation of these tools in our classes and present the outcomes of student surveys. Our instructional focus encompasses VSEPR, Atomic Orbitals, Molecular Orbitals, Skeletal Formula, and Enantiomers. This paper not only serves as a model for educators in general chemistry at secondary school or university levels to incorporate technology into their classrooms but also showcases a collaborative endeavor between Swiss and Thai researchers.

This study introduces (S)-Opto-prop-2, a second-generation photoswitchable ligand designed for precise modulation of β2-adrenoceptor (β2AR). Synthesised by incorporating an azobenzene moiety with propranolol, (S)-Opto-prop-2 exhibited a high PSScis (photostationary state for cis isomer) percentage (∼90 %) and a favourable half-life (>10 days), facilitating diverse bioassay measurements. In vitro, the cis-isomer displayed substantially higher β2AR binding affinity than the trans-isomer (1000-fold), making (S)-Opto-prop-2 one of the best photoswitchable GPCR (G protein-coupled receptor) ligands reported so far. Molecular docking of (S)-Opto-prop-2 in the X-ray structure of propranolol-bound β2AR followed by site-directed mutagenesis studies, identified D1133.32, N3127.39 and F2896.51 as crucial residues that contribute to ligand-receptor interactions at the molecular level. In vivo efficacy was assessed using a rabbit ocular hypertension model, revealing that the cis isomer mimicked propranolol\'s effects in reducing intraocular pressure, while the trans isomer was inactive. Dynamic optical modulation of β2AR by (S)-Opto-prop-2 was demonstrated in two different cAMP bioassays and using live-cell confocal imaging, indicating reversible and dynamic control of β2AR activity using the new photopharmacology tool. In conclusion, (S)-Opto-prop-2 emerges as a promising photoswitchable ligand for precise and reversible β2AR modulation with light. The new tool shows superior cis-on binding affinity, one of the largest reported differences in affinity (1000-fold) between its two configurations, in vivo efficacy, and dynamic modulation. This study contributes valuable insights into the evolving field of photopharmacology, offering a potential avenue for targeted therapy in β2AR-associated pathologies.