Insights on the comparative affinity of ribonucleic acids with plant-based beta carboline alkaloid, harmine: Spectroscopic, calorimetric and computational evaluation
Ontology highlight
ABSTRACT:
SUBMITTER: Sarkar P
PROVIDER: S-EPMC11295990 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Human serum albumin (HSA), an abundant plasma protein, binds to various ligands, acting as a transporter for numerous endogenous and exogenous substances. Galantamine (GAL), an alkaloid, treats cognitive decline in mild to moderate Alzheimer's disease and other memory impairments. A vital step in pharmacological profiling involves the interaction of plasma protein with the drugs, and this serves as an essential platform for pharmaceutical industry advancements. This study is carried out to understand the binding mechanism of GAL with HSA using computational and experimental approaches. Molecular docking revealed that GAL preferentially occupies Sudlow's site I, i.e., binds to subdomain IIIA. The results unveiled that GAL binding does not induce any conformational change in HSA and hence does not compromise the functionality of HSA. Molecular dynamics simulation (250 ns) deciphered the stability of the HSA-GAL complex. We performed the fluorescence binding and isothermal titration calorimetry (ITC) to analyze the actual binding of GAL with HSA. The results suggested that GAL binds to HSA with a significant binding affinity. ITC measurements also delineated thermodynamic parameters associated with the binding of GAL to HSA. Altogether, the present study deciphers the binding mechanism of GAL with HSA.
| S-EPMC9521020 | biostudies-literature
Project description:Direct FXa inhibitors are an important class of bioactive molecules (rivaroxaban, apixaban, edoxaban, and betrixaban) applied for thromboprophylaxis in diverse cardiovascular pathologies. The interaction of active compounds with human serum albumin (HSA), the most abundant protein in blood plasma, is a key research area and provides crucial information about drugs' pharmacokinetics and pharmacodynamic properties. This research focuses on the study of the interactions between HSA and four commercially available direct oral FXa inhibitors, applying methodologies including steady-state and time-resolved fluorescence, isothermal titration calorimetry (ITC), and molecular dynamics. The HSA complexation of FXa inhibitors was found to occur via static quenching, and the complex formation in the ground states affects the fluorescence of HSA, with a moderate binding constant of 104 M-1. However, the ITC studies reported significantly different binding constants (103 M-1) compared with the results obtained through spectrophotometric methods. The suspected binding mode is supported by molecular dynamics simulations, where the predominant interactions were hydrogen bonds and hydrophobic interactions (mainly π-π stacking interactions between the phenyl ring of FXa inhibitors and the indole moiety of Trp214). Finally, the possible implications of the obtained results regarding pathologies such as hypoalbuminemia are briefly discussed.
| S-EPMC10002493 | biostudies-literature
Project description:The prevalence of Alzheimer's disease (AD) has been a major health concern for a long time. Despite recent progress, there is still a strong need to develop effective disease-modifying therapies. Several drugs have already been approved to retard the progression of AD-related symptoms; however, there is a need to develop an effective carrier system for the delivery of drugs to combat such diseases. In recent years, various biological macromolecules, including proteins, have been used as carriers for drug delivery. Irisin is a beneficial hormone in such diseases, including AD and related pathologies. Herein, the interaction mechanism of irisin with AD drugs such as memantine, galantamine, and fluoxetine is investigated. Fluorescence studies revealed that the above drugs bind to irisin with significant affinity, with fluoxetine having the highest binding affinity. Isothermal titration calorimetry (ITC) complemented the spontaneous binding of these drugs with irisin, delineating various associated thermodynamic and binding parameters. Molecular docking further validated the fluorescence and ITC results and unfolded the mechanism that hydrogen bonding governs the binding of fluoxetine to irisin with a significant binding score, i.e., -6.3 kcal/mol. We believe that these findings provide a promising solution to fight against AD as well as a platform for further research to utilize irisin in the drug-delivery system for an effective therapeutic strategy.
| S-EPMC9180407 | biostudies-literature
Project description:Protein-ligand interaction studies are useful to determine the molecular mechanism of the binding phenomenon, leading to the establishment of the structure-function relationship. Here, we report the binding of well-known antibiotic sulfonamide drugs (sulfamethazine, SMZ; and sulfadiazine, SDZ) with heme protein myoglobin (Mb) using spectroscopic, calorimetric, ζ potential, and computational methods. Formation of a 1:1 complex between the ligand and Mb through well-defined equilibrium was observed. The binding constants obtained between Mb and SMZ/SDZ drugs were on the order of 104 M-1. SMZ with two additional methyl (-CH3) substitutions has higher affinity than SDZ. Upon drug binding, a notable loss in the helicity (via circular dichroism) and perturbation of the three-dimensional (3D) protein structure (via infrared and synchronous fluorescence experiments) were observed. The binding also indicated the dominance of non-polyelectrolytic forces between the amino acid residues of the protein and the drugs. The ligand-protein binding distance signified high probability of energy transfer between them. Destabilization of the protein structure upon binding was evident from differential scanning calorimetry results and ζ potential analyses. Molecular docking presented the best probable binding sites of the drugs inside protein pockets. Thus, the present study explores the potential binding characteristics of two sulfonamide drugs (with different substitutions) with myoglobin, correlating the structural and energetic aspects.
| S-EPMC8851458 | biostudies-literature
Project description:Although single-lipid bilayers are usually considered models of eukaryotic plasma membranes, their research drops drastically when it comes to exclusively anionic lipid membranes. Being a major anionic phospholipid in the inner leaflet of eukaryote membranes, phosphatidylserine-constituted lipid membranes were occasionally explored in the form of multilamellar liposomes (MLV), but their inherent instability caused a serious lack of efforts undertaken on large unilamellar liposomes (LUVs) as more realistic model membrane systems. In order to compensate the existing shortcomings, we performed a comprehensive calorimetric, spectroscopic and MD simulation study of time-varying structural features of LUV made from 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS), whereas the corresponding MLV were examined as a reference. A substantial uncertainty of UV/Vis data of LUV from which only Tm was unambiguously determined (53.9 ± 0.8 °C), along with rather high uncertainty on the high-temperature range of DPPS melting profile obtained from DSC (≈50-59 °C), presumably reflect distinguished surface structural features in LUV. The FTIR signatures of glycerol moiety and those originated from carboxyl group serve as a strong support that in LUV, unlike in MLV, highly curved surfaces occur continuously, whereas the details on the attenuation of surface features in MLV were unraveled by molecular dynamics.
| S-EPMC9865892 | biostudies-literature
Project description:ObjectiveSeveral β-carboline alkaloids (βCBs), such as harmine, harmaline, harmane, and nor-harmane, are effective for Alzheimer's disease mouse models. They can be found in some plants, common foodstuffs, and blank plasma of various mammals. However, whether these compounds in mammals are exogenous or endogenous remain unclear.MethodsThe exposure levels of βCBs and of neurotransmitters in plasma and tissues of pup rats, aging rats, mice of different physiological states, and healthy volunteers were detected by using UPLC-MS/MS. Plasma and tissue samples from 110 newborn rats up to 29 days old at 11 sampling points were collected and were analyzed to determine the concentration variation of βCBs in the developmental phase of newborn rats. The plasma of rats aged 2 to 18 months was used to detect the variation trend of βCBs and with some neurotransmitters. The plasma samples of normal C57BL/6 mice, APP/PS1 double transgenic mice, and scopolamine-induced memory impairment mice were collected and were analyzed to compare the difference of βCBs in different physiological states. The exposure levels of βCBs such as harmine, harmaline, and harmane in plasma of 550 healthy volunteers were also detected and analyzed on the basis of gender, race, and age.ResultsResults showed that harmine was the main compound found in rats, mice, and human, which can be detected in a newborn rat plasma (0.16 ± 0.03 ng/ml) and brain (0.33 ± 0.14 ng/g) without any exogenous consumption. The concentration of harmine in rat plasma showed a decreasing trend similar to the exposure levels of neurotransmitters such as 5-hydroxytryptamine, acetylcholine chloride, glutamic acid, tyrosine, and phenylalanine during the growth period of 18 months. The harmine exposure in rats and human indicates high dependence on the physiological and pathological status such as aging, gender, and race.ConclusionThe dynamic changes of harmine exposure in different animals and human, in vivo, at developmental and physiological states indicate that harmine is a naturally and widely distributed endogenous substance in different mammals and human. In addition to exogenous ingestion, spontaneous synthesis might be another important source of harmine in mammals, which should be verified by further experiment.
| S-EPMC8794950 | biostudies-literature
Project description:Huperzine A (HupA), an alkaloid found in the club moss Huperzia Serrata, has been in use for centuries in Chinese traditional medicine to treat dementia owing to its ability to inhibit the cholinergic enzyme acetylcholinesterase (AChE), thus acting as an acetylcholinesterase inhibitor (AChEI). An imbalance of metal ions in the brain is linked to Alzheimer's disease (AD) pathology. Transferrin (Tf) is a crucial player in iron homeostasis, thus highlighting its significance in AD. This study explores the plausible binding of HupA with Tf using molecular docking, molecular dynamics (MD) simulation, and free energy landscape (FEL) analyses. The docking results show that HupA binds to the functionally active region of Tf by forming three hydrogen bonds with Thr392, Glu394, and Ser688 and several hydrophobic interactions. The MD simulation analyses show that HupA binding is stable with Tf, causing minimal changes to the protein conformation. Moreover, principal component analysis (PCA) and FEL also depict the stable binding of HupA with Tf without any significant fluctuations. Further, fluorescence-based binding suggested excellent binding affinity of HupA with Tf affirming in silico observations. Isothermal titration calorimetry (ITC) advocated the spontaneous binding of HupA with Tf. This study provides an insight into the binding mechanism of HupA with Tf, and overall, the results show that HupA, after required experimentations, can be a better therapeutic agent for treating AD while targeting Tf.
| S-EPMC9631745 | biostudies-literature
Project description:Harmine, a ?-carboline alkaloid, is a high affinity inhibitor of the dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) protein. The DYRK1A gene is located within the Down Syndrome Critical Region (DSCR) on chromosome 21. We and others have implicated DYRK1A in the phosphorylation of tau protein on multiple sites associated with tau pathology in Down Syndrome and in Alzheimer's disease (AD). Pharmacological inhibition of this kinase may provide an opportunity to intervene therapeutically to alter the onset or progression of tau pathology in AD. Here we test the ability of harmine, and numerous additional ?-carboline compounds, to inhibit the DYRK1A dependent phosphorylation of tau protein on serine 396, serine 262/serine 356 (12E8 epitope), and threonine 231 in cell culture assays and in vitro phosphorylation assays. Results demonstrate that the ?-carboline compounds (1) potently reduce the expression of all three phosphorylated forms of tau protein, and (2) inhibit the DYRK1A catalyzed direct phosphorylation of tau protein on serine 396. By assaying several ?-carboline compounds, we define certain chemical groups that modulate the affinity of this class of compounds for inhibition of tau phosphorylation.
| S-EPMC3089604 | biostudies-literature
Project description:Dairy mastitis is a disease of dairy cattle caused by a variety of pathogenic microorganisms which has biought huge economic losses aused huge economic losses to the world. In this paper, Harmine derivatives and tetrahydro-β-carboline derivatives synthesized by the splice method are shown to have a good inhibitory effect on the pathogenic bacteria of dairy mastitis. The results of a bacteriostatic test on pathogenic bacteria of dairy cow mastitis (S. dysgalactiae, S. pyogenes, B. subtilis and P. vulgaris) showed that compound 7l had the best bacteriostatic effect on Streptococcus dysgalactiae, with a mic value of 43.7 μ g/mL. When the concentration of 7l was 1 × MIC and 2 × MIC, it had a significant inhibitory effect on Streptococcus dysgalactiae, and there was almost no growth of Streptococcus dysgalactiae at 4 × MIC. The binding properties of target compound 7l to amine oxidase [flavin-containing] A protein were simulated by the molecular docking technique. The ligand 7l achieved strong binding with the receptor through three hydrogen bonds. The hydrogen bonds were amino acid residues thr-52, arg-51 and ser-24, which are the main force for the compound to bind to active sites.
| S-EPMC9104299 | biostudies-literature
Project description:Manzamines are complex polycyclic marine-derived β-carboline alkaloids with reported anticancer, immunostimulatory, anti-inflammatory, antibacterial, antiviral, antimalarial, neuritogenic, hyperlipidemia, and atherosclerosis suppression bioactivities, putatively associated with inhibition of glycogen synthase kinase-3, cyclin-dependent kinase 5, SIX1, and vacuolar ATPases. We hypothesized that additional, yet undiscovered molecular targets might be associated with Manzamine A's (MZA) reported pharmacological properties. We report here, for the first time, that MZA selectively inhibited a 90 kDa ribosomal protein kinase S6 (RSK1) when screened against a panel of 30 protein kinases, while in vitro RSK kinase assays demonstrated a 10-fold selectivity in the potency of MZA against RSK1 versus RSK2. The effect of MZA on inhibiting cellular RSK1 and RSK2 protein expression was validated in SiHa and CaSki human cervical carcinoma cell lines. MZA's differential binding and selectivity toward the two isoforms was also supported by computational docking experiments. Specifically, the RSK1-MZA (N- and C-termini) complexes appear to have stronger interactions and preferable energetics contrary to the RSK2-MZA ones. In addition, our computational strategy suggests that MZA binds to the N-terminal kinase domain of RSK1 rather than the C-terminal domain. RSK is a vertebrate family of cytosolic serine-threonine kinases that act downstream of the ras-ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, which phosphorylates substrates shown to regulate several cellular processes, including growth, survival, and proliferation. Consequently, our findings have led us to hypothesize that MZA and the currently known manzamine-type alkaloids isolated from several sponge genera may have novel pharmacological properties with unique molecular targets, and MZA provides a new tool for chemical-biology studies involving RSK1.
| S-EPMC8467814 | biostudies-literature