Affinity Sites Research Articles

Investigation into the Interaction between Penicillin-Resistant and Penicillin-Susceptible Gonococcal Penicillin-Binding Protein 2 and Target Phenolic Ligands through Molecular Docking Studies and Structure-Activity Relationship Analysis.

Gonococcal infections present a notable public health issue, and the major approach for treatment involves using β-lactam antibiotics that specifically target penicillin-binding protein 2 (PBP2) in Neisseria gonorrhoeae. This study examines the influence of flavonoids, namely, rutin, on the structural changes of PBP2 in both penicillin-resistant (FA6140) and penicillin-susceptible (FA19) strains. The research starts by clarifying the structural effects of certain mutations, such as the insertion of an aspartate residue at position 345 (Asp-345a), in the PBP2. The strain FA6140, which is resistant to penicillin, shows specific changes that lead to a decrease in penicillin binding. These mutations, namely, P551S and F504L, have a significant impact on the pace at which acylation occurs and the stability of the strain under high temperatures. Molecular docking analyses investigate the antibacterial activities of rutin and other phytocompounds, emphasising rutin's exceptional binding affinity and its potential as an inhibitor of PBP2. Quercetin and protocatechuic acid have encouraging antibacterial effectiveness, with quercetin displaying characteristics similar to those of drugs. Molecular dynamics simulations offer a detailed comprehension of the interactions between flavonoids and PBP2, highlighting rutin's exceptional antioxidant effects and strong affinity for the substrate binding site. The study's wider ramifications pertain to the pressing requirement for antiviral treatments, namely, in the context of the ongoing COVID-19 epidemic. Flavonoids have a strong affinity for binding to PBP2, indicating their potential as inhibitors to impair cell wall formation in N. gonorrhoeae. Ultimately, this study provides extensive knowledge on the interactions between proteins and ligands, the dynamics of the structure, and the ability of flavonoids to combat penicillin-resistant N. gonorrhoeae bacteria. The verified simulation outcomes establish a basis for the creation of potent inhibitors and medicinal therapies to combat infectious illnesses.

Exploring peptidomes of by-products generated during chhurpi production using Lactobacillus delbrueckii WS4 for identification of novel bioactive peptides.

The considerable value of whey is evident from its significant potential applications and contributions to the functional food and nutraceutical market. The by-products were individually obtained during functional chhurpi and novel soy chhurpi cheese production using defined lactic acid bacterial strains of Sikkim Himalaya's traditional chhurpi. Hydrolysis of substrate proteins by starter proteinases resulted in a comparable peptide content in whey and soy whey which was associated with antioxidant and ACE inhibition potential. Peptidome analysis of Lactobacillus delbrueckii WS4 whey and soy whey revealed the presence of several bioactive peptides including the multifunctional peptides PVVVPPFLQPE and YQEPVLGPVRGPFPIIV. In silico analyses predicted the antihypertensive potential of whey and soy whey peptides with strong binding affinity for ACE active sites. QSAR models predicted the highest ACE inhibition potential (IC50) for the β-casein-derived decapeptide PVRGPFPIIV (0.95 μM) and the Kunitz trypsin inhibitor protein-derived nonapeptide KNKPLVVQF (16.64 μM). Chhurpi whey and soy whey can be explored as a valuable source of diverse and novel bioactive peptides for applications in designer functional foods development.

Inhibition of α-glucosidase activity and intestinal glucose transport to assess the in vivo anti-hyperglycemic potential of dodecyl-acylated phlorizin and polydatin derivatives.

A diet containing natural active compounds that can inhibit the hydrolytic activity of α-glucosidase on carbohydrates and intestinal glucose absorption is an effective means of controlling postprandial hyperglycemia. Phlorizin and polydatin as phenolic glycosides have a high affinity for the catalytic site of α-glucosidase, but exhibited unsatisfactory competitive inhibitory capacity, with an IC50 of 0.97 and >2 mM, respectively. However, dodecyl-acylated derivatives of phlorizin and polydatin exerted α-glucosidase inhibitory capacity, with an IC50 of 55.10 and 70.95 μM, respectively, which were greatly enhanced and much stronger than that of acarbose with an IC50 of 2.46 mM. The SPR assay suggested the high affinity of dodecyl phlorizin and dodecyl polydatin to α-glucosidase with equilibrium dissociation constant (KD) values of 12.0 and 7.9 μM, respectively. Both dodecyl phlorizin and dodecyl polydatin reduced the catalytic ability of α-glucosidase by reversible noncompetitive and uncompetitive mixed inhibition, which bind noncovalently to the allosteric site 2 through hydrogen bonds and hydrophobic interactions, thereby inducing the secondary structure unfolding and intrinsic fluorescence quenching of α-glucosidase. Confocal microscopy detection visually showed significant inhibitory effects on FITC-labeled glucose uptake in intestinal Caco-2 cells by phlorizin, polydatin, dodecyl phlorizin and dodecyl polydatin. In addition, based on the differentiated Caco-2 cell monolayer model, dodecyl phlorizin and dodecyl polydatin suppressed intestinal glucose transport more effectively than phlorizin and polydatin, suggesting that they were promising in vivo hypoglycemic active compounds.

Characterization and discrimination of volatile organic compounds and α-glucosidase inhibitory activity of soybeans (Glycine max L.) during solid-state fermentation with Eurotium cristatum YL-1

In this study, the influence of solid-state fermentation (SSF) using probiotic Eurotium cristatum on the change of volatile organic compounds (VOCs) and α-glucosidase inhibition activity of soybeans was investigated. A total of 46 VOCs were characterized via headspace gas chromatography-ion mobility spectrometry (HS-GC-IMS), the majority of which were aldehydes (17), alcohols (10), and ketones (7). SSF by E. cristatum drastically affected the flavor characteristics of soybeans, and the levels of unpleasant beany flavor components, such as hexanal-D, 1-octen-3-ol, 1-hexanol-D, 1-hexanol-M, heptanal-M, 1-pentanol, heptanal-D, and 2-pentyl furan were all substantially decreased by 50% after 15 days of SSF, while volatiles with floral, caramel, and desirable flavors such as pentanal-D, methylpropanal, 2-propanol, and propyl acetate drastically (p < 0.05) increased by 1.1-, 19.2-, 3.6-, and 2.6-fold, respectively. Key aroma-active compounds analysis revealed that 18 VOCs (ROAV, relative odor activity value ≥ 1) play a great role in shaping the flavor characteristics of the soybean samples. After 15 days of SSF, the ROAV values of methylpropanal, 2-propanol, and propyl acetate drastically (p < 0.05) increased to 8.48, 63.88, and 11.29, respectively, which greatly contributed to the desirable flavor characteristics of fermented soybeans. Furthermore, E. cristatum greatly improved the α-glucosidase inhibitory activity of soybean by 22.4% after 15 days fermentation, which was closely correlated with the accumulated phenolic compounds during SSF. Molecular docking showed that genistein and daidzein have high binding affinity for α-glucosidase active sites, primarily driven by hydrogen bonds and hydrophobic interactions. These results demonstrated that soybeans fermented with E. cristatum substantially improved the flavor characteristics and α-glucosidase inhibitory effect, and were greatly helpful to promote the application of soybeans in food products.

The density-threshold affinity:Calculating lipid binding affinities from unbiased coarse-grained molecular dynamics simulations.

Many membrane proteins are sensitive to their local lipid environment. As structural methods for membrane proteins have improved, there is growing evidence of direct, specific binding of lipids to protein surfaces. Unfortunately the workhorse of understanding protein-small molecule interactions, the binding affinity for a given site, is experimentally inaccessible for these systems. Coarse-grained molecular dynamics simulations can be used to bridge this gap, and are relatively straightforward to learn. Such simulations allow users to observe spontaneous binding of lipids to membrane proteins and quantify localized densities of individual lipids or lipid fragments. In this chapter we outline a protocol for extracting binding affinities from these localized distributions, known as the "density threshold affinity." The density threshold affinity uses an adaptive and flexible definition of site occupancy that alleviates the need to distinguish between "bound'' lipids and bulk lipids that are simply diffusing through the site. Furthermore, the method allows "bead-level" resolution that is suitable for the case where lipids share binding sites, and circumvents ambiguities about a relevant reference state. This approach provides a convenient and straightforward method for comparing affinities of a single lipid species for multiple sites, multiple lipids for a single site, and/or a single lipid species modeled using multiple forcefields.

Structural basis of nuclear transport for NEIL DNA glycosylases mediated by importin-alpha

NEIL glycosylases, including NEIL1, NEIL2, and NEIL3, play a crucial role in the base excision DNA repair pathway (BER). The classical importin pathway mediated by importin α/β and cargo proteins containing nuclear localization sequences (NLS) is the most common transport mechanism of DNA repair proteins to the nucleus. Previous studies have identified putative NLSs located at the C-terminus of NEIL3 and NEIL1. Crystallographic, bioinformatics, calorimetric (ITC), and fluorescence assays were used to investigate the interaction between NEIL1 and NEIL3 putative NLSs and importin-α (Impα). Our findings showed that NEIL3 contains a typical cNLS, with medium affinity for the major binding site of Impα. In contrast, crystallographic analysis of NEIL1 NLS revealed its binding to Impα, but with high B-factors and a lack of electron density at the linker region. ITC and fluorescence assays indicated no detectable affinity between NEIL1 NLS and Impα. These data suggest that NEIL1 NLS is a non-classical NLS with low affinity to Impα. Additionally, we compared the binding mode of NEIL3 and NEIL1 with Mus musculus Impα to human isoforms HsImpα1 and HsImpα3, which revealed interesting binding differences for HsImpα3 variant. NEIL3 is a classical medium affinity monopartite NLS, while NEIL1 is likely to be an unclassical low-affinity bipartite NLS. The base excision repair pathway is one of the primary systems involved in repairing DNA. Thus, understanding the mechanisms of nuclear transport of NEIL proteins is crucial for comprehending the role of these proteins in DNA repair and disease development.

In Vivo and in Silico Based Evaluation of Antidiabetic Potential of an Isolated Flavonoid from Allium hookeri in Type 2 Diabetic Rat Model.

Allium hookeri (F: Liliaceae), an indigenous plant of Manipur, India, is traditionally used to treat various diseases and disorders like diabetes, hypertension, and stomach ache. In our previous study, the methanol extract of the plant showed significant antidiabetic potential in rats. In the present study, we evaluated the antidiabetic potential of a flavonoid compound named MEA isolated from the methanolic leaf extract of A. Hookeri in rats. Additionally, we assessed the compound's mode of action through the molecular docking study. The MEA reduced the blood glucose level from 317±12.8 to 99.4±6.67 mg/dl after 21 days of treatment. Besides, MEA also restored the body weights and other biochemical parameters including lipid profile significantly compared to the diabetic group (p<0.001). The histoarchitecture of the pancreatic tissues of the MEA treated group was also improved compared to the diabetic group. In the docking study, the compound showed good binding affinity in the active binding site of the two structures of pancreatic beta-cell SUR1 (Sulfonylurea Receptor 1) subunit with CDocker energy -31.556 kcal/mol and -39.703 kcal/mol, respectively. The compound MEA was found to be drug-like with non-carcinogenic, non-mutagenic and non-irritant properties. These findings indicate the antidiabetic potential of MEA, which might act by modulating the pancreatic beta-cell SUR1 subunit present in the KATP channel. Hence, the MEA would be a promising lead molecule to develop new antidiabetic drug candidates of the future.

Advanced Equilibrium Studies for the Synergetic Impact of Polyaniline on the Adsorption of Rhodamine B Dye by Polyaniline/Coal Composite.

The synergetic improvement effect of the polyaniline (PANI) hybridization process on the adsorption of rhodamine B dye (RB) by PANI/coal hybrid material (PANI/C) has been evaluated using both traditional equilibrium modeling and advanced isotherm investigations. The composite was prepared by polymerizing polyaniline in the presence of coal fractions with a surface area of 27.7 m2/g. The PANI/C hybrid has an improved capacity to adsorb RB dye (423.5 mg/g) in comparison to coal particles (254.3 mg/g). The maintained increase in the elimination properties of PANI/C has been illustrated using the steric characteristics of active site density (Nm) as well as the total number of adsorbed RB on a single active site (n). However, the incorporation of PANI did not yield any substantial impact on the existing active sites' quantity, but the hybridization processes greatly influenced the selectivity and affinity of each active site, in addition to the aggregation characteristics of the dye as it interacts with the composite's surface. Whereas raw coal can only adsorb three molecules of RB, each active site throughout the PANI/C surface can adsorb approximately eight RB molecules. This is also evidence of RB dye adsorption in a vertical arrangement, which involves multimolecular processes. The Gaussian energy (4.01-5.59 kJ/mol) and adsorption energy (-4.34-4.68 kJ/mol) revealed the controllable impact of physical mechanisms. These mechanisms may include van der Waals forces, dipole-dipole interactions, and hydrogen bonds (<30 kJ/mol). The thermodynamic functions, such as enthalpy, internal energy, and entropy, that have been assessed provide evidence supporting the exothermic and spontaneous nature of the RB uptake processes by PANI/C.

Synthesis, Cytotoxicity, Antioxidant Activity, DFT Calculations, and Docking Studies of New Pyridine-Malonate Derivatives as Potential Anticancer Agents

A series of new pyridine-malonate derivatives were synthesized and fully characterized by 1HNMR, 13CNMR, FTIR, and elemental analysis. Their molecular geometry and chemical reactivity have been investigated using DFT calculations. The cytotoxicity of all synthesized compounds was assessed against two human cancer cell lines (MCF-7 and A-2780) using the MTT assay. Among them, compounds 2a, 2c, 2e, and 2g showed comparable or more potent cytotoxicity toward the MCF-7 cells than the reference drug docetaxel (IC50 = 0.34–0.47 vs. 0.50 µM). In contrast, only compound 2g showed more potent cytotoxicity against the A-2780 cell line compared to the standard (IC50 = 0.36 vs. 0.42 µM). The docking study revealed a good affinity for the active site of the human topoisomerase-IIβ enzyme, which may explain the promising cytotoxicity of these classes of molecules. The radical scavenging activity of the respective compounds was studied using DPPH radical scavenging assay and it was found that most of the compounds are moderate DPPH radical scavengers compared to the standard drugs BHA and BHT.

A glutathione S-transferase and a cytochrome P450 may confer cyhalofop-butyl resistance in Leptochloa chinensis (L.) Nees

BackgroundLeptochloa chinensis (L.) Nees is a troublesome weed across China in rice fields, and a suspected L. chinensis resistant population (R) that has survived the recommended field dose of cyhalofop-butyl was collected in a rice field of Hunan Province, China. In this study, we aimed to determine the acetyl-CoA carboxylase-inhibiting herbicide resistance profile of this R population and to investigate its mechanisms of resistance to cyhalofop-butyl. ResultsCompared with the susceptible population (S), the R population was confirmed to be 18.9-, 3.2-, 4.1-, 3.6- and 5.8- fold resistant to the APP herbicides cyhalofop-butyl, haloxyfop-P-methyl, clodinafop-propargyl, metamifop and fenoxaprop-P-ethyl, respectively. ACCase gene sequencing analysis revealed no known resistance mutations for TSR in the R population. Pretreatment with the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) and cytochrome P450 (CYP450) inhibitor malathion reversed resistance to cyhalofop-butyl. The GST gene GSTU1 and CYP450 gene CYP707A5 were constitutively upregulated in the R population according to RNA-seq analysis and RT-qPCR verification. The molecular docking results indicated a good affinity of the active site for five APP herbicides with GSTU1 and CYP707A5. ConclusionThis study shows that the GSTU1 and CYP707A5 genes expressed highly in the R population may be responsible for cyhalofop-butyl resistance in L. chinensis.

Single-nucleotide variants within heart enhancers increase binding affinity and disrupt heart development.

Transcriptional enhancers direct precise gene expression patterns during development and harbor the majority of variants associated with phenotypic diversity, evolutionary adaptations, and disease. Pinpointing which enhancer variants contribute to changes in gene expression and phenotypes is a major challenge. Here, we find that suboptimal or low-affinity binding sites are necessary for precise gene expression during heart development. Single-nucleotide variants (SNVs) can optimize the affinity of ETS binding sites, causing gain-of-function (GOF) gene expression, cell migration defects, and phenotypes as severe as extra beating hearts in the marine chordate Ciona robusta. In human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, a SNV within a human GATA4 enhancer increases ETS binding affinity and causes GOF enhancer activity. The prevalence of suboptimal-affinity sites within enhancers creates a vulnerability whereby affinity-optimizing SNVs can lead to GOF gene expression, changes in cellular identity, and organismal-level phenotypes that could contribute to the evolution of novel traits or diseases.

In silico identification of five binding sites on the SARS-CoV-2 spike protein and selection of seven ligands for such sites

To contribute to the development of products capable of complexing with the SARS-CoV-2 spike protein, and thus preventing the virus from entering the host cell, this work aimed at discovering binding sites in the whole protein structure, as well as selecting substances capable of binding efficiently to such sites. Initially, the three-dimensional structure of the protein, with all receptor binding domains in the closed state, underwent blind docking with 38 substances potentially capable of binding to this protein according to the literature. This allowed the identification of five binding sites. Then, those substances with more affinities for these sites underwent pharmacophoric search in the ZINC15 database. The 14,329 substances selected from ZINC15 were subjected to docking to the five selected sites of the spike protein. The ligands with more affinities for the protein sites, as well as the selected sites themselves, were used in the de novo design of new ligands that were also docked to the binding sites of the protein. The best ligands, regardless of their origins, were used to form complexes with the spike protein, which were subsequently used in molecular dynamics simulations and calculations of ligands affinities to the protein through the molecular mechanics/Poisson–Boltzmann surface area method (MMPBSA). Seven substances with good affinities to the spike protein (-12.9 to −20.6 kcal/mol), satisfactory druggability (Bioavailability score: 0.17 to 0.55), and low acute toxicity to mice (LD50: 751 to 1421 mg/kg) were selected as potentially useful for the future development of new products to manage COVID-19 infections. Communicated by Ramaswamy H. Sarma

Targeted transplantation of engineered mitochondrial compound promotes functional recovery after spinal cord injury by enhancing macrophage phagocytosis

Mitochondria are crucial in sustaining and orchestrating cellular functions. Capitalizing on this, we explored mitochondrial transplantation as an innovative therapeutic strategy for acute spinal cord injury (SCI). In our study, we developed an engineered mitochondrial compound tailored to target macrophages within the SCI region. Sourced from IL-10-induced Mertkhi bone marrow-derived macrophages, we conjugated a peptide sequence, cations-cysteine-alanine-glutamine-lysine (CAQK), with the mitochondria, optimizing its targeting affinity for the injury site. Our data demonstrated that these compounds significantly enhanced macrophage phagocytosis of myelin debris, curtailed lipid buildup, ameliorated mitochondrial dysfunction, and attenuated pro-inflammatory profiles in macrophages, both in vitro and in vivo. The intravenously delivered mitochondrial compounds targeted the SCI epicenter, with macrophages being the primary recipients. Critically, they promoted tissue regeneration and bolstered functional recovery in SCI mice. This study heralds a transformative approach to mitochondrial transplantation in SCI, spotlighting the modulation of macrophage activity, phagocytosis, and phenotype.

In-silico Studies of Quinazolinone Analogues to Distinguish their Hypothetical Binding Mode using the X-ray crystal Structure Human carbon Anhydrase II (HCAII) Enzyme Complex with Sugar Sulfamate for Anticonvulsant Activity

The quinazolinone moiety is a significant pharmacophore that depicts various types of pharmacological activities as shown in recent exhaustive ligatures. Quinazolinone exhibit potent central nervous system (CNS) activities like anti-anxiety, analgesic, anti-inflammatory and anticonvulsant. To develop these views and application profiles, attempt have been made to report a drug/ligand or receptor/protein interactions by identifying the suitable active site against X-ray crystal structure of Human Carbonic Anhydrase II (HCA II) enzyme for anticonvulsant activity using Vlife MDS version 4.6 Software because the protein-ligand interaction plays a significant role in structural based drug designing. The interaction was evaluated based on the score comparison between quinazolinone derivatives with sugar sulfamate. The quinazolinone ring forms hydrophobic and hydrogen bond contacts amino acid residues. The ligands 4t and 4s were shown to possess minimum dock score i.e. minimum binding energy in Kcal/mole i.e. these molecules has more affinity for the active site of the receptor. Molecules with low dock score and binding energy show more affinity towards the receptor. The data reported in this article may be helpful for the medicinal chemists who are working in this area.

In Vitro Characterization of the Interactions of Human Serum Albumin with Rosuvastatin and Atorvastatin Using Fluorescence Spectroscopy and Molecular Modeling

Human serum albumin (HSA) is one of the most important transporters for drugs in the systemic circulation. In this study, we investigated the interaction of rosuvastatin (ROS) and atorvastatin (ATO) with HSA. Binding of a drug molecule to HSA significantly affects the pharmacokinetics of the drug as it increases drug solubility in plasma, decreases toxicity and protects molecules from oxidation. This study was made using fluorescence spectroscopy and molecular modeling approach. Fluorescence spectra were recorded for two different statins brands at seven different concentrations. The results revealed that both statins (ROS and ATO) cause the fluorescence quenching of the HSA solution. ROS and ATO binds strongly to HSA with the binding constant (Kb) of 1.0246×106 and 0,9018×106, respectively. In addition, it was observed that high concentrations of ATO cause a shift of the emission maximum towards longer wavelengths (red-shift), which may be due to the unfolding of protein chains or denaturation. Furthermore, it was calculated that HSA possesses one binding site for ROS and ATO. Results from molecular docking showed that ROS has a higher affinity for Sudlow site I compared to Sudlow site II and the main binding forces are hydrogen bonds. ATO has nearly equal affinity for both binding sites on HSA, and the main binding forces are hydrophobic interactions.

Asciminib - ABL Kinase Inhibitor in the Treatment of Philadelphia Chromosome Positive Chronic Myeloid Leukemia: Chemistry and Pharmacology Perspectives

Abstract: Asciminib, also known as ACP-196, is the FDA-approved low-molecular ABL kinase inhibitor. The ABL kinase is a non-receptor tyrosine kinase that helps in cell growth and survival and is a key player in the development of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The BCR-ABL fusion protein, which is formed by chromosomal translocation in CML and Ph+ ALL, results in the constitutive activation of ABL kinase, leading to uncontrolled cell growth and proliferation. To have a high binding affinity for the active site of the enzyme, structural biology and computer-aided drug design (CADD) concepts were applied to the design of asciminib so that it could specifically target the ABL kinase enzyme. The drug was synthesized and characterized in a laboratory. In its pharmacological studies, it has shown that asciminib is a potent and selective inhibitor of ABL kinase. Phase I clinical trials assessed its safety and efficacy, revealing that it is effective against tumors while causing minimal discomfort to patients. In addition to this, it was able to induce apoptosis and a cytogenetic response as well as inhibit the proliferation of CML and Ph+ALL cells in patients with CML. As this trial gave a positive response, phase II and III trials were conducted. In that sense, asciminib has shown to be highly effective, with response rates of over 90% in patients with these diseases. The safety and efficacy of asciminib were also evaluated in combination with other drugs, such as tyrosine kinase inhibitors and immunomodulatory drugs, and the results were promising. Overall, the discovery and development of asciminib showed that by using the concepts of pharmacology and CADD, a drug with a 90% positive rate response can be developed with a high tolerance level and lower side effects

Computational Study on the Enzyme-Ligand Relationship between Cannabis Phytochemicals and Human Acetylcholinesterase: Implications in Alzheimer's Disease.

Cannabis has shown promise in treating various neurological disorders, including Alzheimer's disease (AD). AD is a devastating neurodegenerative disorder that affects millions of people worldwide. Current treatments for AD are limited and are not very effective. This study investigated the enzyme-ligand relationship between nine active components of cannabis and human acetylcholinesterase (HuAChE) enzyme, which is significant in AD. Specifically, computational methods such as quantum mechanics, molecular docking, molecular dynamics, and free energy calculations were used to identify the cannabis phytochemicals with the highest HuAChE affinity and to understand the specific binding mechanisms involved. Our results showed that cannabichromene and cannabigerol were the cannabis phytochemicals with the highest affinity for HuAChE, with cannabichromene exhibiting the greatest binding energy. However, both substances showed lower affinity than that of the pharmaceutical drug donepezil. This study suggests that cannabichromene has a specific affinity for the peripheral anionic site (PAS) and acyl-binding pocket (ABP), while cannabigerol predominantly binds to PAS. Also, it was found that cannabichromene has a specific affinity for PAS and ABP, while cannabigerol predominantly binds to PAS. Our findings suggest that cannabichromene and cannabigerol are potential therapeutic agents, but further research is needed to validate their effectiveness. The specific binding mechanisms identified may also provide helpful information for the design of more effective cannabis-based drugs. Overall, this study provides valuable insights into the potential of cannabis-based drugs for treating neurological diseases.

Gd3+ Complexes for MRI Detection of Zn2+ in the Presence of Human Serum Albumin: Structure-Activity Relationships.

Zn2+-responsive magnetic resonance imaging (MRI) contrast agents are typically composed of a Gd chelate conjugated to a Zn2+-binding moiety via a linker. They allow for Zn2+ detection in the presence of human serum albumin (HSA). In order to decipher the key parameters that drive their Zn2+-dependent MRI response, we designed a pyridine-based ligand, PyAmC2mDPA, and compared the properties of GdPyAmC2mDPA to those of analogue complexes with varying Gd core, Zn-binding moiety, or linker sizes. The stability constants determined by pH potentiometry showed the good selectivity of PyAmC2mDPA for Gd3+ (log KGd = 16.27) versus Zn2+ (log KZn = 13.58), proving that our modified Zn2+-binding DPA moiety prevents the formation of previously observed dimeric species. Paramagnetic relaxation enhancement measurements indicated at least three sites that are available for GdPyAmC2mDPA binding on HSA, as well as a 2-fold affinity increase when Zn2+ is present (KD = 170 μM versus KDZn = 60 μM). Fluorescence competition experiments provided evidence of the higher affinity for site II vs site I, as well as the importance of both the Zn-binding part and the Gd core in generating enhanced HSA affinity in the presence of Zn2+. Finally, an analysis of nuclear magnetic relaxation dispersion (NMRD) data suggested a significantly increased rigidity for the Zn2+-bound system, which is responsible for the Zn2+-dependent relaxivity response.

Charge dynamics of amino acids fingerprints and the effect of density on FinFET-based Electrolyte-gated sensor

This work presents the charge dynamics and the effect of the density of amino acids on a sensing surface with the help of analytical modelling. We have implemented an in-house simulator incorporating the Gouy-Chapman-Stern and Site-Binding model to capture the perturbations in the proton affinity of reactive sites with the variation of amino acid density over a sensing surface. The results of the models are explained for Alanine, Glutamic Acid and Histidine with their α-carboxylic terminal immobilized on the sensor surface. The results show that an increase in amino acid density on the sensing surface over a certain limit deviates the fingerprints of the proton affinity away from the affinity of the reactive sites of individual amino acids. The effect of different electrolyte concentrations on steric hindrance is also captured for Alanine and Glutamic Acid. Finally, we used a junctionless FinFET to model unique signatures of amino acids down to a single molecule.

Design, synthesis, docking studies and biological screening of 2-pyrimidinyl-2, 3-dihydro-1H-naphtho [1, 2-e][1, 3] oxazines as potent tubulin polymerization inhibitors

A series of novel substituted 2-pyrimidinyl-2,3-dihydro-1H-naphtho[1,2-e][1, 3]oxazine analogs have been designed and synthesized based on structure-activity relationships from 2-naphthol, substituted pyrimidinyl amines and formalin through ring closure by one-pot three component reaction. These derivatives were evaluated for their in vitro cytotoxicity, cell cycle assay and their inhibitory effect on tubulin polymerization. From the MTT assay, it is clear that most of the synthesized compounds displayed potent cytotoxic activities on HeLa (cervical cancer) and B16F10 (melanoma) cancerous cell lines. The compounds 6b and 6k were found to be more effective against HeLa cell lines and exhibited significant cytotoxicity (with IC50 values 1.26 ± 0.12 µM and 1.16 ± 0.27 µM respectively), accumulation of HeLa cells in G2/M phase and exhibiting induced apoptosis. The immunohistochemistry and fluorescence assays showed that these compounds 6b and 6k inhibited the microtubule assembly in human cervical cancer cells (HeLa) at 2 µM concentration. Furthermore, molecular docking studies of these molecules revealed their better-fit potential as anticancer molecules and have a high affinity for colchicine binding site, indicating more inhibitory potential at the cellular level. Our studies suggest that the newly synthesized compounds may become promising leads for the development of new anti-cancer agents. Communicated by Ramaswamy H. Sarma