High Affinity Binding Research Articles

Design, synthesis and evaluation of novel norfloxacin analogs as potent anticancer and antioxidant agents.

Aim: To synthesize a novel series of norfloxacin analogs and to evaluate biological activity. Methodology: Novel norfloxacin analogs were synthesized and characterized by NMR and mass spectrometry. Antiproliferative and antioxidant properties were studied. Results: Compound 2f was the most potent against HeLa cell-line with 100% inhibition of cell viability IC50=3.1±0.2μM. All compounds exhibit moderate to excellent antioxidant properties. Docking study demonstrates higher binding affinity of compounds with respective anticancer (B-cell lymphoma-2) and (tyrosinase) antioxidant targets. In silico absorption, distribution, metabolism and excretion profile of compounds proves all synthesized compounds follow Lipinski's rule of drug likeness, non toxic and possess passive gastrointestinal absorption. Conclusion: The biological profile suggest that the synthesized norfloxacin analogs can be a novel scaffold for future anticancer drug development.

Semisynthetic guanidino lipoglycopeptides with potent in vitro and in vivo antibacterial activity.

Gram-positive bacterial infections present a major clinical challenge, with methicillin- and vancomycin-resistant strains continuing to be a cause for concern. In recent years, semisynthetic vancomycin derivatives have been developed to overcome this problem as exemplified by the clinically used telavancin, which exhibits increased antibacterial potency but has also raised toxicity concerns. Thus, glycopeptide antibiotics with enhanced antibacterial activities and improved safety profiles are still necessary. We describe the development of a class of highly potent semisynthetic glycopeptide antibiotics, the guanidino lipoglycopeptides, which contain a positively charged guanidino moiety bearing a variable lipid group. These glycopeptides exhibited enhanced in vitro activity against a panel of Gram-positive bacteria including clinically relevant methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant strains, showed minimal toxicity toward eukaryotic cells, and had a low propensity for resistance selection. Mechanistically, guanidino lipoglycopeptides engaged with bacterial cell wall precursor lipid II with a higher binding affinity than vancomycin. Binding to both wild-type d-Ala-d-Ala lipid II and the vancomycin-resistant d-Ala-d-Lac variant was confirmed, providing insight into the enhanced activity of guanidino lipoglycopeptides against vancomycin-resistant isolates. The in vivo efficacy of guanidino lipoglycopeptide EVG7 was evaluated in a S. aureus murine thigh infection model and a 7-day sepsis survival study, both of which demonstrated superiority to vancomycin. Moreover, the minimal to mild kidney effects at supratherapeutic doses of EVG7 indicate an improved therapeutic safety profile compared with vancomycin. These findings position guanidino lipoglycopeptides as candidates for further development as antibacterial agents for the treatment of clinically relevant multidrug-resistant Gram-positive infections.

Prediction of Protein-Drug Interactions, Pharmacophore Modeling, and Toxicokinetics of Novel Leads for Type 2 Diabetes Treatment.

Small heterocyclic compounds have been crucial in pioneering advances in type 2 diabetes treatment. There has been a dramatic increase in the pharmacological development of novel heterocyclic derivatives aimed at stimulating the activation of Glucokinase (GK). A pharmaceutical intervention for diabetes is increasingly targeting GK as a legitimate target. Diabetes type 2 compromises Glucokinase's function, an enzyme vital for maintaining the balance of blood glucose levels. Medicinal substances strategically positioned to improve type 2 diabetes management are used to stimulate the GK enzyme using heterocyclic derivatives. The research endeavor aimed to craft novel compounds, drawing inspiration from the inherent coumarin nucleus found in nature. The goal was to evoke the activity of the glucokinase enzyme, offering a tailored approach to mitigate the undesired side effects typically associated with conventional therapies employed in the treatment of type 2 diabetes. Coumarin, sourced from nature's embrace, unfolds as a potent and naturally derived ally in the quest for innovative antidiabetic interventions. Coumarin was extracted from a variety of botanical origins, including Artemisia keiskeana, Mallotus resinosus, Jatropha integerrima, Ferula tingitana, Zanthoxylum schinifolium, Phebalium clavatum, and Mammea siamensis. This inclusive evaluation was conducted on Muybridge's digital database containing 53,000 hit compounds. The presence of the coumarin nucleus was found in 100 compounds, that were selected from this extensive repository. Utilizing Auto Dock Vina 1.5.6 and ChemBioDraw Ultra, structures generated through this process underwent docking analysis. Furthermore, these compounds were accurately predicted online log P using the Swiss ADME algorithm. A predictive analysis was conducted using PKCSM software on the primary compounds to assess potential toxicity. Using Auto Dock Vina 1.5.6, 100 coumarin derivatives were assessed for docking. Glucokinase (GK) binding was significantly enhanced by most of these compounds. Based on superior binding characteristics compared with Dorzagliatin (standard GKA) and MRK (co-crystallized ligand), the top eight molecules were identified. After further evaluation through ADMET analysis of these eight promising candidates, it was confirmed that they met the Lipinski rule of five and their pharmacokinetic profile was enhanced. The highest binding affinity was demonstrated by APV16 at -10.6 kcal/mol. A comparison between the APV16, Dorzagliatin and MRK in terms of toxicity predictions using PKCSM indicated that the former exhibited less skin sensitization, AMES toxicity, and hepatotoxicity. Glucokinase is most potently activated by 100 of the compound leads in the database of 53,000 compounds that contain the coumarin nucleus. APV12, with its high binding affinity, favorable ADMET (adjusted drug metabolic equivalents), minimal toxicity, and favorable pharmacokinetic profile warrants consideration for progress to in vitro testing. Nevertheless, to uncover potential therapeutic implications, particularly in the context of type 2 diabetes, thorough investigations and in-vivo evaluations are necessary for benchmarking before therapeutic use, especially experiments involving the STZ diabetic rat model.

Photocorrosion suppression of copper sulfide via hybridization with amino-functionalized metal–organic framework for natural sunlight-driven photocatalysis

Natural sunlight-driven photocatalysis has been considered as an energy sustainable strategy for the synthesis of fine chemicals, since natural sunlight is inexhaustible. Copper sulfide (CuS) with broad light absorption holds great promise for natural sunlight utilization, while hole-induced photocorrosion seriously hampers its photoactivity and photostability. Herein, we inhibited the photocorrosion by hybridizing CuS with amino-functionalized metal–organic framework of NH2-MIL-125(Ti) (NM125) to fabricate a Z-scheme heterojunction. Taking advantage of high binding affinity of amino group and copper ion, CuS nanoparticles (NPs) were in situ anchored on NM125 surface via amino group-assisted coordination. Characterization results suggested the diffusion-controlled charge migration in NM125@CuS(x) hybrids, where photoinduced electrons in conduction band (CB) of NM125 transferred to valence band (VB) of CuS, and then combined here. The Z-scheme charge transport could timely consume the photogenerated holes of CuS, and spatially separated the charge carriers. As a result, the obtained NM125@CuS(x) catalysts were highly efficient and stable in natural sunlight-driven Phillips-Ladenburg reaction in air, providing serial benzimidazoles with excellent yields (90–98%). Such natural sunlight-driven photocatalysis system efficiently utilized natural sunlight to synthesize high-value fine chemicals in open air at mild conditions, which opens up a sustainable avenue for the green development of fine chemical engineering.

Locuaz: An in-silico platform for protein binders optimization.

Engineering high-affinity binders targeting specific antigenic determinants remains a challenging and often daunting task, requiring extensive experimental screening. Computational methods have the potential to accelerate this process, reducing costs and time, but only if they demonstrate broad applicability and efficiency in exploring mutations, evaluating affinity, and pruning unproductive mutation paths. In response to these challenges, we introduce a new computational platform for optimizing protein binders towards their targets. The platform is organized as a series of modules, performing mutation selection and application, molecular dynamics (MD) simulations to sample conformations around interaction poses, and mutation prioritization using suitable scoring functions. Notably, the platform supports parallel exploration of different mutation streams, enabling in silico high-throughput screening on HPC systems. Furthermore, the platform is highly customizable, allowing users to implement their own protocols. The source code is available at https://github.com/pgbarletta/locuaz and documentation is at https://locuaz.readthedocs.io/. Available at https://github.com/pgbarletta/suppl_info_locuaz.

Discovery of Curcuminoids as Pancreatic Lipase Inhibitors from Medicine-and-Food Homology Plants

Researchers are increasingly interested in discovering new pancreatic lipase inhibitors as anti-obesity ingredients. Medicine-and-food homology plants contain a diverse set of natural bioactive compounds with promising development potential. This study screened and identified potent pancreatic lipase inhibitors from 20 commonly consumed medicine-and-food homology plants using affinity ultrafiltration combined with spectroscopy and docking simulations. The results showed that turmeric exhibited the highest pancreatic lipase-inhibitory activity, and curcumin, demethoxycurcumin, and bisdemethoxycurcumin were discovered to be potent pancreatic lipase inhibitors within the turmeric extract, with IC50 values of 0.52 ± 0.04, 1.12 ± 0.05, and 3.30 ± 0.08 mg/mL, respectively. In addition, the enzymatic kinetics analyses demonstrated that the inhibition type of the three curcuminoids was the reversible competitive model, and curcumin exhibited a higher binding affinity and greater impact on the secondary structure of pancreatic lipase than found with demethoxycurcumin or bisdemethoxycurcumin, as observed through fluorescence spectroscopy and circular dichroism. Furthermore, docking simulations supported the above experimental findings, and revealed that the three curcuminoids might interact with amino acid residues in the binding pocket of pancreatic lipase through non-covalent actions, such as hydrogen bonding and π-π stacking, thereby inhibiting the pancreatic lipase. Collectively, these findings suggest that the bioactive compounds of turmeric, in particular curcumin, can be promising dietary pancreatic lipase inhibitors for the prevention and management of obesity.

A molecular anion pump.

Pumping ions against a concentration gradient through protein-based transporters is a cornerstone of numerous biological processes. Mimicking this function by using artificial receptors remains a daunting challenge, mainly because of the difficulties in balancing between the requirement for high binding affinities and precise and on-demand ion capture and release properties. We report a trimeric hydrazone photoswitch-based receptor that converts light energy into work by actively transporting chloride anion against a gradient through a dichloromethane liquid membrane, functioning as a molecular pump. The system manifests ease of synthesis, bistability, excellent photoswitching properties, and superb ON-OFF binding properties (difference of up to six orders of magnitude).

In vivo absorption, in vitro simulated digestion, and fecal fermentation properties of Imperata cylindrica polysaccharides and their effects on gut microbiota

Recently we have investigated polysaccharide from Imperata cylindrica (ICP) for its physicochemical structure and biological activities. However, the digestion characteristics have yet to be understood. This study investigated the digestion and metabolism characteristics of ICP through in vivo fluorescence tracking, in vitro simulated digestion, fecal fermentation experiments, and microbial sequencing. The results showed that ICP significant distribution in the gastrointestinal tract and kidneys. ICP underwent slight degradation during simulated gastric and intestinal digestion. During fecal fermentation, the utilization degree of ICP and the concentration of short-chain fatty acids (SCFAs) increased. ICP promoted the increase of beneficial microbial abundance. To understand the impact of ICP on the integrity and health of intestinal tissues, molecular docking was employed to preliminarily predict the interaction between ICP and key proteins. The results revealed that ICP could recognize and bind to key proteins through high-affinity targeting binding sites.

Telmisartan loaded lipid nanocarrier as a potential repurposing approach to treat glioma: characterization, apoptosis evaluation in U87MG cells, pharmacokinetic and molecular simulation study

The study explores anticancer potential of telmisartan (TS) loaded lipid nanocarriers (TLNs) in glioma cells as a potential repurposing nanomodality along with estimation of drug availability at rat brain. Experimental TLNs were produced by previously reported method and characterized. In vitro anticancer efficacy of experimental TLNs was estimated by MTT, confocal microscopy, and FACs analysis in glioma cells. Plasma and brain pharmacokinetic (PK) parameters were also analysed by LCMS/MS. Spherical, nanosized, homogenous, unilamellar, TLNs were reported having desirable drug loading (9.5% ± 0.6%), negative zeta potential and sustained TS release tendency. FITC-TLNs were sufficiently internalized into U87MG cells line within 0.5 h incubation period. IC50 for TLNs was considerably higher than free TS in the tested glioma cell lines. Further, TLNs induced superior apoptotic effect in U87MG cells than TS. PK (plasma/brain) data depicted higher AUC, V ss, MRT with lower Clt for TLNs suggesting improved bioavailability, in vivo residence and sustained drug availability than free TS administration. Docking studies rationalized in vitro/in vivo results as preferably higher binding affinity (docking score:12.4) was detected for TS with glioma proteins. Further, in vivo studies in glioma bearing xenograft model is underway for futuristic clinical validation of TLNs.

Hesperidin Alleviates Acute Necrotizing Pancreatitis by Activating SIRT1 - Molecular Docking, Molecular Dynamics Simulation, and Experimental Validation.

Acute necrotizing pancreatitis is a serious pancreatic injury with limited effective treatments. This study aims to investigate the therapeutic effects of hesperidin on Larginine- induced acute pancreatitis and its potential targets. The authors induced acute pancreatitis in mice by administering two hourly intraperitoneal injections of L-arginine-HCl, and evaluated the impact of hesperidin on pancreatic and lung tissues, plasma amylase activity, and myeloperoxidase content. Additionally, necrosis and mitochondrial function was tested in primary pancreatic acinar cells. The interactions between hesperidin and proteins involved in necrosis and mitochondrial dysfunction were further invested using in silico molecular docking and molecular dynamic simulations. Hesperidin effectively ameliorated the severity of acute necrotizing pancreatitis by reducing plasma amylase, pancreatic MPO, serum IL-6 levels, pancreatic edema, inflammation, and pancreatic necrosis. Hesperidin also protected against acute pancreatitis-associated lung injury and prevented acinar cell necrosis, mitochondrial membrane potential loss, and ATP depletion. In addition, hesperidin exhibited a high binding affinity with SIRT1 and increased the protein levels of SIRT1. The SIRT1 inhibitor EX527 abolished the protective effect of hesperidin against necrosis in acinar cells. These findings indicate that hesperidin alleviates the severity of acute necrotizing pancreatitis by activating SIRT1, which may provide insight into the mechanisms of natural compounds in treating AP. Hesperidin has potential as a therapeutic agent for acute necrotizing pancreatitis and provides a new approach for novel therapeutic strategies.

Isolation of anti-tumor monoclonal antibodies targeting on MICA/B α3 domain by single B cell technology for colon cancer therapy

Colon cancer (CC) is one of the most common gastrointestinal malignancies. Effectiveness of the existing therapies is limited. Immunotherapy is a promising complementary treatment approach for CC. Major histocompatibility complex class I-related protein A and B (MICA/B) are ligands for NK cells. Shedding of MICA/B from the surface of tumor cells by cleavage of MICA/B at the membrane proxial region in MICA/B α3 structural domain is one of immune evasion strategies leading to escape of cancer cells from immunosurveillance. In this study, we generated a panel of MICA/B monoclonal antibodies (mAbs) and identified one of mAbs, mAb RDM028, that had high binding affinity to MICA/B and recognized a site on MICA/B α3 structural domain that is critically important for cleavage of MICA/B. Our study has further demonstrated that RDM028 augmented the surface expression of MICA/B on HCT-116 human CC cells by inhibiting the MICA/B shedding resulting in the enhanced cyotoxicity of NK cells against HCT-116 human CC cells and mediated anti-tumor activity in nude mouse model of colon cancer. These results indicate that mAb RDM028 could be explored for developing as an effective immuno therapy against CC by targeting the MICA/B α3 domain to promot immunosurveillance mediated by MICA/B-NKG2D interaction.

The Mechanism of Action of the Active Ingredients of Coptidis rhizoma against Porcine Epidemic Diarrhea Was Investigated Using Network Pharmacology and Molecular Docking Technology

The objective of this study was to elucidate the mechanism of action of the active components of Coptidis rhizoma against porcine epidemic diarrhea and to provide a theoretical foundation for further development of novel anti-PED therapeutic agents based on Coptidis rhizoma. The potential targets of Coptidis rhizoma against PEDV were identified through a comprehensive literature review and analysis using the TCMSP pharmacological database, SwissDrugDesign database, GeneCards database, and UniProt database. Subsequently, the STRING database and Cytoscape 3.7.1 software were employed to construct a protein–protein interaction (PPI) network and screen key targets. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted on the identified targets. Molecular docking studies were performed using AutoDock 1.5.7 software to analyze the binding energy and modes of interaction between the active components of Coptidis rhizoma and the target proteins. The PyMOL 2.5.0a0 software was employed to visualize the docking results. Through comprehensive analysis, 74 specific targets of active components of Coptidis rhizoma against PEDV were identified. The core gene targets were screened, and an interaction network diagram was subsequently generated. Ultimately, 14 core targets were identified, with STAT3, ESR1, CASP3, and SRC exhibiting the most significant interactions. GO enrichment analysis revealed a total of 215 molecular items, including 48 biological function items, 139 biological process items, and 28 cellular component items. KEGG enrichment analysis identified 140 signaling pathways. Molecular docking analysis demonstrated that epiberberine and palmatine exhibited high binding affinity with STAT3 protein, worenine showed high binding affinity with ESR1 protein, obacunone exhibited high binding affinity with CASP3 protein, and epiberberine, obacunone, berberine, and berberruine exhibited high binding affinity with SRC protein. A network pharmacology and molecular docking technology approach was employed to screen six important active components of Coptidis rhizoma and four important potential targets against PEDV infection. The findings indicated that the active components of Coptidis rhizoma could serve as promising pharmaceutical agents for the prevention and control of PEDV, with significant potential for clinical application.

Multi-epitope peptide vaccines targeting dengue virus serotype 2 created via immunoinformatic analysis

The Middle East has witnessed a greater spread of infectious Dengue viruses, with serotype 2 (DENV-2) being the most prevalent form. Through this work, multi-epitope peptide vaccines against DENV-2 that target E and nonstructural (NS1) proteins were generated through an immunoinformatic approach. MHC class I and II and LBL epitopes among NS1 and envelope E proteins sequences were predicted and their antigenicity, toxicity, and allergenicity were investigated. Studies of the population coverage denoted the high prevalence of NS1 and envelope-E epitopes among different countries where DENV-2 endemic. Further, both the CTL and HTL epitopes retrieved from NS1 epitopes exhibited high conservancies’ percentages with other DENV serotypes (1, 3, and 4). Three vaccine constructs were created and the expected immune responses for the constructs were estimated using C-IMMSIM and HADDOCK (against TLR 2,3,4,5, and 7). Molecular dynamics simulation for vaccine construct 2 with TLR4 denoted high binding affinity and stability of the construct with the receptor which might foretell favorable in vivo interaction and immune responses.

Investigation of substituent effects on the electronic structure and antiviral activity of favipiravir derivatives for Covid-19 treatment using DFT and molecular docking

In this study, Density-functional theory/Time-dependent density-functional theory (DFT/TDDFT) and Molecular docking method was used to investigate the effect of methyl acetate, tetrahydrofuran and cyanobenzylidene substituents on the electronic structure and antiviral activity of favipiravir for treating COVID-19. The DFT and TDDFT computations were employed using the Gaussian 09 software package. The values were calculated using the 6-311++G(d, p) basis set and the hybrid B3LYP functional method. Autodock vina software was used for simulations to better predictions and to validate the modified compounds' binding affinities and poses. Results of the study indicate that compounds 1 to 6 all displayed a planar structure, where the pyrazine ring, carboxamide, hydroxyl groups, and other substituents are all situated within the same plane. In addition, the energy gaps (Egap) of these six compounds (Cpd 1, 2, 3, 4, 5, and 6) were compared. The significant dipole moment and binding affinity achieved implies a particular orientation for binding within the target protein, signaling the anticipated strength of the binding interaction. In all six compounds, the electrophilic domain is situated in the vicinity of the amine functional group within the carboxamide compound, whereas the nucleophilic domain encompasses both the carbonyl and hydroxyl groups. The most negatively charged sites are susceptible to electrophilic interactions. In conclusion, compounds 5 and 6 exhibit a high binding affinity of the target protein, while compound 6 has a high energy gap, which could enhance its antiviral activity against the COVID-19 virus.

Mechanistic insights into the metabolic pathways of vanillin: unraveling cytochrome P450 interaction mechanisms and implications for food safety.

Vanillin, a key flavor compound found in vanilla beans, is widely used in the food and pharmaceutical industries for its aromatic properties and potential therapeutic benefits. This study presents a comprehensive quantum chemical analysis to elucidate the interaction mechanisms of vanillin with CYP450 enzymes, with a focus on mechanism-based inactivation. Three potential inactivation pathways were evaluated: aldehyde deformylation, methoxy dealkylation, and acetal formation. Aldehyde deformylation was identified as the most energy-efficient, involving the removal of the aldehyde group from vanillin and leading to the formation of benzyne intermediates that could react with the iron porphyrin moiety of CYP450, potentially resulting in enzyme inactivation. Further investigation into the interactions of vanillin with CYP2E1 and CYP1A2 was conducted using molecular docking and molecular dynamics (MD) simulation. The docking analyses supported the findings from DFT studies, wherein vanillin revealed high binding affinities with the studied isozymes. Moreover, vanillin occupied the main binding site in both isozymes, as evidenced by the inclusion of the heme moiety in their binding mechanisms. Employing a 100 ns molecular dynamics simulation, we scrutinized the interaction dynamics between vanillin and the two isozymes of CYP450. The assessment of various MD parameters along with interaction energies revealed that vanillin exhibited stable trajectories and substantial energy stabilization during its interaction with both CYP450 isozymes. These insights can guide future research and ensure the safe application of vanillin, especially in scenarios where it may interact with CYP450 enzymes.

Computational study of novel natural agonists targeting farnesoid X receptor

The farnesoid X receptor (FXR) is a crucial therapeutic target for treating non-alcoholic steatohepatitis (NASH). Although obeticholic acid (OCA) as a FXR agonist presents good efficacy, the safety data such as severe pruritus should be carefully considered. To discover new medications, we screen and choose the optimal compounds from ZINC15 database that may agonistically interact with FXR. We utilized the DS19 software to assist us in conducting the computer-aided structure based virtual screening to discover potential FXR agonists. After LibDock scores were determined by screening, their absorption, distribution, metabolism, excretion and toxicity predictions were examined. To determine the binding affinity between the chosen drugs and FXR, molecule docking was utilized. Molecular dynamics simulation was utilized to evaluate the stabilization of the ligand-FXR complex in its native environment. Higher binding affinity and stability with FXR were observed for ZINC000013374322 and ZINC000006036327, as two novel natural compounds, with lower rodent carcinogenicity, Ames mutagenicity, no hepatotoxicity and non-inhibitors of CYP2D6. They could stably exist in the environment, possess favorable potential energy and exert pharmacological effects at lower doses. Furthermore, ZINC000006036327 had lower skin irritancy and sensitization potential compared to OCA, also suggest the possibility of improved skin itching occurrence. ZINC000013374322 and ZINC000006036327 were found to be the best leading compounds to be FXR agonists. They are chosen as safe candidates for FXR target medicine, which play comparable pharmacological effects at lower doses.

Interaction of Sambiloto (Andrographis paniculata) Bioactive Compound with Milk Protein (Whey and Casein) Through Molecular Docking and Molecular Dynamics Simulation as a Basis for Encapsulation

This research aims for developing immune-boosting products necessary. The active ingredient in Andrographis paniculate (AP) acts as an immunostimulant which can improve the work of the immune system. The first stage of research was a collection of bioactive compounds from KnapSack database of Kanaya, Dr. Duke's Phytochemical and Ethnobotanical were compiled and selected based on the online pass results of each bioactive compound as an immunomodulator and 10 active compounds were obtained which will be continued. The second stage of research was a docking molecular between whey proteins (β-lactoglobulin and α-lactalbumin) with active compounds from AP and casein (α-Casein, β-Casein, and κ-Casein). The highest binding affinity was obtained for α-Casein with Neoandrographolide at -9.2 Kcal/mol. The results of the complex α-Casein with Neoandrographolide (CC) and α-Casein with Neoandrographolide ultraheat (CCT) support the research, namely to function α-Casein as an encapsulant well as a transporter or drug delivery of Neoandrographolide without changing the conformation of casein and disturbing its function. However, the conformation of casein will change drastically during ultraheat treatment to maintain the conformation and binding with the Neoandrographolide ligand. In addition, it supports the simulation results of single α-Casein at ultraheat temperatures which show conformational stability that is not much different from single α-casein and complexes at physiological temperatures

Comprehensive analysis of Indacaterol and Theophylline molecules: insights from DFT, FTIR, Raman, UV, molecular docking, and ADMET studies

In this study, the structural, vibrational, and biological properties of Indacaterol and Theophylline were thoroughly investigated using quantum chemical and spectroscopic methods, and then compared with experimental FTIR, Raman, and UV–Vis data. The analysis revealed that electronegative oxygen and nitrogen atoms in both molecules facilitate charge transfers, resulting in the shortening of C–C bonds. The HOMO–LUMO energy gaps were found to be 4.298 eV for Indacaterol and 5.170 eV for Theophylline, indicating that Indacaterol is more bioactive. The electrophilic index values suggest that Indacaterol is more electrophilic, potentially offering a higher affinity for protein binding. Molecular electrostatic potential surface maps indicated that electrophilic regions are concentrated near the oxygen and nitrogen atoms, which was corroborated by molecular docking analysis. Binding affinities of Indacaterol and Theophylline to COVID-19 main protease proteins were calculated, showing higher affinities for Indacaterol. Drug likeness, physicochemical, and ADMET results suggest that both molecules have favorable pharmacokinetic profiles and comply with Lipinski’s Rule of Five, indicating effective absorption and distribution. Overall, the study suggests that Indacaterol and Theophylline could function as inhibitors against SARS-CoV-2 and COVID-19 proteins, with Indacaterol potentially being more effective.

Sulfated Alginate for Biomedical Applications.

Alginate (Alg) polymers have received much attention due to the mild conditions required for gel formation and their good bio-acceptability. However, due to limited interactions with cells, many drugs, and biomolecules, chemically modified alginates are of great interest. Sulfated alginate (S-Alg) is a promising heparin-mimetic that continues to be investigated both as a drug molecule and as a component of biomaterials. Herein, the S-Alg literature of the past five years (2017-2023) is reviewed. Several methods used to synthesize S-Alg are described, with a focus on new advances in characterization and stereoselectivity. Material fabrication is another focus and spans bulk materials, particles, scaffolds, coatings, and part of multicomponent biomaterials. The new application of S-Alg as an antitumor agent is highlighted together with studies evaluating safety and biodistribution. The high binding affinity of S-Alg for various drugs and heparin-binding proteins is exploited extensively in biomaterial design to tune the encapsulation and release of these agents and this aspect is covered in detail. Recommondations include publishing key material properties to allow reproducibility, careful selection of appropriate sulfation strategies, the use of cross-linking strategies other than ionic cross-linking for material fabrication, and more detailed toxicity and biodistribution studies to inform future work.

Novel Inhibitor of Glutamate-Cysteine Ligase Catalytic Subunit against Tribolium castaneum: High-Throughout Virtual Screening, Molecular Docking and Dynamics Simulation, and Bioassay.

The enzyme glutamate-cysteine ligase catalytic subunit (Gclc) is a rate-limiting enzyme in the biosynthesis of glutathione that is involved in antioxidant defense, detoxification of xenobiotics, and/or its metabolites and regulates the cell cycle and immune function. Therefore, Gclc presents an appealing target for the development of novel insecticides. In this study, we conducted high-throughput virtual screening from the ZINC20 database and identified three compounds with high binding affinity to the Tribolium castaneum Gclc (TcGclc). Ultimately, we selected ZINC000032992384 due to its superior stability and lowest binding energy, as determined through molecular dynamics simulations. Bioassay results revealed that the IC50 value of ZINC000032992384 was 19.70 μM lower than that of BSO (49.67 μM). Furthermore, the larval mortality in the ZINC000032992384 treated group was 63.8%, significantly higher than that of the controls (29.1% in the dichlorvos group and 6.4% in the acetone group). This study provides novel insights for the development of a Gclc-targeted inhibitor as a potent insecticide based on the interaction between receptors and ligands.