MOLECULAR DOCKING STUDIES OF BERBERINE DERIVATIVE AS NOVEL MULTITARGET PCSK9 AND HMGCR INHIBITORS

Hypercholesterolemia is a high risk for cardiovascular diseases, stroke, and mortality. Multitarget directed ligands (MTDLs) with dual inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) are the potential targets for the treatment of hyperlipidemia. In this work, a novel series of Berberine (BBR) derivatives was designed based on molecular docking to serve as MTDLs for PCSK9 and HMGCR. The binding energy of BBR derivatives was investigated, which confirmed that all the designed compounds showed better binding energy than the parent BBR for both enzymes. The effect of different benzenesulfonyl ring substituents was explored to improve the binding affinity. The obtained results indicated that there are significant differences in their interactions and mode of binding. All 24 designed compounds were identified as the potent multitarget inhibitors because the increase of hydrogen bond, hydrophobic and electrostatic interactions were observed. Among them, 12 could be selected as the best candidate for further study as potential multitarget PCSK9 and HMGCR inhibitors for anti-hypercholesterolemia. The obtained result suggested that the introduction of the nitro- group plays a vital role in the binding pose of the BBR derivative. Finally, in silico study confirmed that most of the compounds pass the drug likeliness properties

Additive effects on cotton dyeing with dye extract from achiote seeds

Cotton yarns have been pretreated with the additives, such as chitosan, microcrystalline chitosan, quaternized chitosan &aqueous extract from the fruit of Diospyros mollis Griff, as well as with the commercial formaldehyde-free cationic fixingagent (Sera® Fast C-NC) & alum (post-mordanting), and their dyeing fastness properties are studied. These treated cottonyarns are then dyed with the annatto dye extract from Bixa orellana L. (Achiote) seeds and tested for different propertiesincluding K/S value, light fastness, and wash fastness. Pre-treatment of cotton yarn with chitosan or microcrystallinechitosan solution (together with glyoxal cross-linking) or quaternized chitosan, or Sera® Fast C-NC before dyeing, shows abetter color depth (K/S) and improved wash fastness properties in comparison to yarn with alum post-mordanting and theuntreated cotton yarn. Improved light fastness is also obtained on inclusion of the anti-oxidant ascorbic acid in the posttreatmentprotocol. These additive treatments thus offer considerable potential for the improved annatto dyeing of cotton

In Silico Investigation of Estrogen Receptor Alpha Inhibition by Alkyleneoxyberberine Derivatives

Breast cancer remains one of the most prevalent malignancies worldwide, with estrogen receptor alpha (ERα) playing a crucial role in its development and progression. In this study, we investigated the binding interactions and stability of berberrubine (1) and 9-(4-methyl phenethoxy) berberine (2) as potential ERα inhibitors using computational approaches. Molecular docking was performed to evaluate binding affinities and interactions, followed by molecular dynamics (MD) simulations to assess the stability and conformational changes of the ERα-ligand complexes. The binding free energy was further analyzed using Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) calculations to identify key energy contributions. The results demonstrated that (2) exhibited stronger and more stable binding to ERα than (1), though both were less potent than 4-hydroxytamoxifen (OHT), a standard ERα inhibitor. Additionally, ERα-(2) interacts with key residues ALA350, GLU353, and ARG394, while exhibiting stronger van der Waals interactions than ERα-(1), consistent with the MMGBSA energy component analysis. The study provides insights into the molecular mechanisms of ERα inhibition by berberine derivatives and highlights their potential as lead compounds for further development in breast cancer therapy

Antimicrobial and Efflux Pump Inhibitory Activity of Caffeoylquinic Acids from Artemisia absinthium against Gram-Positive Pathogenic Bacteria

Background: Traditional antibiotics are increasingly suffering from the emergence of multidrug resistance amongst pathogenic bacteria leading to a range of novel approaches to control microbial infections being investigated as potential alternative treatments. One plausible antimicrobial alternative could be the combination of conventional antimicrobial agents/antibiotics with small molecules which block multidrug efflux systems known as efflux pump inhibitors. Bioassay-driven purification and structural determination of compounds from plant sources have yielded a number of pump inhibitors which acted against gram positive bacteria. Methodology/Principal Findings: In this study we report the identification and characterization of 4′,5′-O-dicaffeoylquinic acid (4′,5′-ODCQA) from Artemisia absinthium as a pump inhibitor with a potential of targeting efflux systems in a wide panel of Gram-positive human pathogenic bacteria. Separation and identification of phenolic compounds (chlorogenic acid, 3′,5′-ODCQA, 4′,5′-ODCQA) was based on hyphenated chromatographic techniques such as liquid chromatography with post column solid-phase extraction coupled with nuclear magnetic resonance spectroscopy and mass spectroscopy. Microbial susceptibility testing and potentiation of well know pump substrates revealed at least two active compounds; chlorogenic acid with weak antimicrobial activity and 4′,5′-ODCQA with pump inhibitory activity whereas 3′,5′-ODCQA was ineffective. These intitial findings were further validated with checkerboard, berberine accumulation efflux assays using efflux-related phenotypes and clinical isolates as well as molecular modeling methodology. Conclusions/Significance: These techniques facilitated the direct analysis of the active components from plant extracts, as well as dramatically reduced the time needed to analyze the compounds, without the need for prior isolation. The calculated energetics of the docking poses supported the biological information for the inhibitory capabilities of 4′,5′-ODCQA and furthermore contributed evidence that CQAs show a preferential binding to Major Facilitator Super family efflux systems, a key multidrug resistance determinant in gram-positive bacteria.National Institutes of Health (U.S.) (grant R01GM59903)National Institutes of Health (U.S.) (grant R01AI050875)Netherlands Organization for Scientific Research (VICI grant 700.56.442)Massachusetts Technology Transfer Center (MTTC)National Institutes of Health (U.S.) (grant 5U54MH084690-02

Additive effects on cotton dyeing with dye extract from achiote seeds

466-474Cotton yarns have been pretreated with the additives, such as chitosan, microcrystalline chitosan, quaternized chitosan & aqueous extract from the fruit of Diospyros mollis Griff, as well as with the commercial formaldehyde-free cationic fixing agent (Sera® Fast C-NC) & alum (post-mordanting), and their dyeing fastness properties are studied. These treated cotton yarns are then dyed with the annatto dye extract from Bixa orellana L. (Achiote) seeds and tested for different properties including K/S value, light fastness, and wash fastness. Pre-treatment of cotton yarn with chitosan or microcrystalline chitosan solution (together with glyoxal cross-linking) or quaternized chitosan, or Sera® Fast C-NC before dyeing, shows a better color depth (K/S) and improved wash fastness properties in comparison to yarn with alum post-mordanting and the untreated cotton yarn. Improved light fastness is also obtained on inclusion of the anti-oxidant ascorbic acid in the post-treatment protocol. These additive treatments thus offer considerable potential for the improved annatto dyeing of cotton

A mass spectrometric investigation of novel quadruplex DNA-selective berberine derivatives

ESI mass spectrometry was used to assess the binding of 13-substituted, 5-nitro-2-phenylindolyl- and 2-naphthalenyl-based berberine derivatives to inter- and intramolecular G-quadruplex DNA molecules. In contrast with the parent berberine, the compounds showed selectivity for quadruplex over duplex DNA and stabilised the quadruplex structure. They represent a new class of quadruplex DNA-selective ligands. © 2010 The Royal Society of Chemistry

A Potential of Mutant Yeast Strain for Improvement Arabica Coffee Fermentation Process

Arabica coffee is a worldwide popular beverage. Coffee fermentation is important process to enhance the coffee flavor quality. Microorganisms involved in the process are the main factor affecting coffee quality. This study aims to apply the new starter culture of Wickerhamomyces anomalus UV22-3, a UV mutant strain, for coffee fermentation and to improve arabica coffee beverage quality. The results showed that W. anomalus UV22-3 as a starter culture for coffee fermentation could enhance the coffee flavor quality compared to the control experiment (without inoculum). Fermented arabica coffee by strain UV22-3 showed a higher cupping score than wild type and a control condition with unique cupping notes. According to the flavor profile evaluated by Q-graders, the result of this sensory evaluation is 82. Microbial population in the fermentation broth was evaluated. The total yeast number was stable, while the total bacteria was higher after 24 h of strain UV22-3 fermentation. The pH value slightly decreased when the total dissolved solid increased. This research is one alternative to improve the quality of coffee in Thailand by using a novel yeast strain

Chemical Profiling and in vitro Testing for PCSK9 Inhibition of Coffee Cascara Extract

Coffee cascara is a by-product generated from coffee processing. It has been discarded as an agricultural waste.  In order to reduce the environmental problems caused by coffee processing, this study aimed to investigate the effect of fresh coffee cascara extract (CCE) on the inhibition of PCSK9 which is an enzyme that can increase low-density plasma lipoprotein (LDL) cholesterol by destructing LDL receptor.  Moreover, the CCE chemical profile was identified by the thin-layer chromatography (TLC) technique together with diffusion-ordered NMR spectroscopy (DOSY). The chemical profile analysis results showed that trigonelline, caffeine, and chlorogenic acid were present in CCE, and its PCSK9 inhibitory activity screening showed that CCE at concentrations of 0.25 and 0.50 mg/mL reduced the amount of PCSK9 by 72 and 78%, respectively.  These results revealed that coffee cascara provides novel applications in the nutraceutical industry

A mechanism for the extension and unfolding of parallel telomeric G-quadruplexes by human telomerase at single-molecule resolution

30 pags., 10 figs., 1 tab.Telomeric G-quadruplexes (G4) were long believed to form a protective structure at telomeres, preventing their extension by the ribonucleoprotein telomerase. Contrary to this belief, we have previously demonstrated that parallel-stranded conformations of telomeric G4 can be extended by human and ciliate telomerase. However, a mechanistic understanding of the interaction of telomerase with structured DNA remained elusive. Here, we use single-molecule fluorescence resonance energy transfer (smFRET) microscopy and bulk-phase enzymology to propose a mechanism for the resolution and extension of parallel G4 by telomerase. Binding is initiated by the RNA template of telomerase interacting with the G-quadruplex; nucleotide addition then proceeds to the end of the RNA template. It is only through the large conformational change of translocation following synthesis that the G-quadruplex structure is completely unfolded to a linear product. Surprisingly, parallel G4 stabilization with either small molecule ligands or by chemical modification does not always inhibit G4 unfolding and extension by telomerase. These data reveal that telomerase is a parallel G-quadruplex resolvase.Cancer Council NSW RG 11-07 Tracy M Bryan, Cancer Institute NSW Aaron Lavel Moye, Australian Research Council FL140100027 Antoine M van Oijen, Ernest and Piroska Major Foundation Scott B Cohen, Natural Sciences and Engineering Research Council of Canada, Masad J Damha Centre of Excellence for Innovation in Chemistry PERCH-CIC Siritron Samosorn Research Unit of Natural Products and Organic Synthesis for Drug Discovery NPOS 405/2560 Siritron Samosorn Cancer Council NSW RG 16-10 Tracy M Brya