Docking Studies Research Articles

Molecular insights into the antioxidant and anticancer properties: A comprehensive analysis through molecular modeling, docking, and dynamics studies.

Plants are rich sources of therapeutic compounds that often lack the side effects commonly found in synthetic chemicals. Researchers have effectively synthesized pharmaceuticals from natural sources, taking inspiration from traditional medicine, in their pursuit of modern drugs. This study aims to evaluate the phenolic and flavonoid content of Solanum virginianum seeds using different solvent extracts, enzymatic assays including 2,2-diphenyl-1-picrylhydrazylactivity, reducing power, and superoxide activity. Our phytochemical screening identified active compounds, such as phenols, flavonoids, tannins, and alkaloids. The methanol extract notably possesses higher levels of total phenolic and flavonoid content in comparison to the other extracts. The results highlight the superior antioxidant activity of methanol-extracted leaves, demonstrated by their exceptional IC50 values, which surpass the established standard. In this study, molecular docking techniques were used to assess the binding affinity and to predict the binding conformation of the compounds. Quercetin 3-O beta- d-galactopyranoside displayed a binding energy of -8.35 kcal/mol with several important amino acid residues, PHE222, TRP440, ILE184, LEU192, VAL221, LEU218, SER185, and ALA188. Kaempferol 3-O-beta- l-glucopyranoside exhibited a binding energy of -8.33 kcal/mol, interacting with specific amino acid residues including ALA 441, VAL318, VAL322, MET307, ILI409, GLY442, and PHE439. The results indicate that the methanol extract has a distinct composition of biologically active constituents compared to the other extracts. Overall, seeds exhibit promise as natural antioxidants and potential agents for combating cancer. This study highlights the significance of utilizing the therapeutic capabilities of natural compounds and enhancing our comprehension of their pharmacological characteristics.

Identification and Molecular Docking Analysis of Angiotensin-Converting Enzyme Inhibitors from Finger Millet (Eleusine coracana).

Hypertension remains a significant global health concern, contributing significantly to cardiovascular diseases and mortality rates. The inhibition of angiotensin-converting enzyme (ACE) plays a crucial role in alleviating high blood pressure. We investigated the potential of finger millets (Eleusine coracana) as a natural remedy for hypertension by isolating and characterizing its ACE-inhibitory compound. First, we evaluated the ACE-inhibitory activity of the finger millet ethanol extract and subsequently proceeded with solvent fractionation. Among the solvent fractions, the ethyl acetate fraction exhibited the highest ACE inhibitory activity and was further fractionated. Using preparative high-performance liquid chromatography, the ethyl acetate fraction was separated into four subfractions, with fraction 2 (F2) exhibiting the highest ACE inhibitory activity. Subsequent 1H-nuclear magnetic resonance (NMR) and 13C-NMR analyses confirmed that the isolated compound from F2 was catechin. Furthermore, molecular docking studies indicated that catechin has the potential to act as an ACE inhibitor. These findings suggest that finger millets, particularly as a source of catechin, have the potential to be used as a natural antihypertensive.

Bioselective and Radiopaque Zinc-Biopolymeric Complex-Based Porous Biomaterials Promote Mammalian Tissue Ingrowth In Vivo While Inhibiting Microbial Biofilm Gene Expression and Biofilm Formation.

Metal-organic complexes have shown astounding bioactive properties; however, they are rarely explored as biomaterials. Recent studies showed that carboxymethyl-chitosan (CMC) genipin-conjugated zinc biomimetic scaffolds have unique bioselective properties. The biomaterial was reported to be mammalian cell-friendly; at the same time, it was found to discourage microbial biofilm formation on its surface, which seemed to be a promising solution to addressing the problem of trauma-associated biofilm formation and development of antimicrobial resistance. However, the mechanically frail characteristics and zinc overload raise concerns and limit the potential of the said biomaterials. Hence, the present work is focused on improving the strength of the earlier scaffold formulations, testing its in vivo efficacy and reaffirming its action against biofilm-forming microbe Staphylococcus aureus. Scaling up of CMC proportion increased rigidity, and 8% CMC was found to be the ideal concentration for robust scaffold fabrication. Freeze-dried CMC scaffolds with or without genipin (GP) cross-linking were conjugated with zinc using 2 M zinc acetate solution. Characterization results indicated that the CMC-Zn scaffolds, without genipin, showed mechanical properties close to bone fillers, resist in vitro enzymatic degradation until 4 weeks, are porous in nature, and have radiopacity close to mandibular bones. Upon implantation in a subcutaneous pocket of Wistar rats, the scaffolds showed tissue in-growth with simultaneous degradation without any signs of toxicity past 28 days. Neither were there any signs of toxicity in any of the vital organs. Considering many superior properties among the other formulations, the CMC-Zn scaffolds were furthered for biofilm studies. CMC-Zn showed negligible S. aureus biofilm formation on its surface as revealed by an alamar blue-based study. RT-PCR analysis revealed that CMC-Zn downregulated the expression of pro-biofilm effector genes such as icaC and clfB. A protein docking study predicted the inhibitory mechanism of CMC-Zn. Although it binds strongly when alone, at high density, it may cause inactivation of the transmembrane upstream activators of the said genes, thereby preventing their dimerization and subsequent inactivation of the effector genes. In conclusion, zinc-conjugated carboxymethyl-chitosan scaffolds are mechanically robust, porous, yet biodegradable, harmless to the host in the long term, they are radiopaque and prevent biofilm gene expression in notorious microbes; hence, they could be a suitable candidate for bone filler applications.

Ultrathin TiS2@N,S-Doped Carbon Hybrid Nanosheets as Highly Efficient Photoresponsive Antibacterial Agents.

Nanobactericides are employed as a promising class of nanomaterials for eradicating microbial infections, considering the rapid resistance risks of conventional antibiotics. Herein, we present a pioneering approach, reporting the synthesis of two-dimensional titanium disulfide nanosheets coated by nitrogen/sulfur-codoped carbon nanosheets (2D-TiS2@NSCLAA hybrid NSs) using a rapid l-ascorbic acid-assisted sulfurization of Ti3C2Tx-MXene to achieve efficient alternative bactericides. The as-developed materials were systematically characterized using a suite of different spectroscopy and microscopy techniques, in which the X-ray diffraction/Raman spectroscopy/X-ray photoelectron spectroscopy data confirm the existence of TiS2 and C, while the morphological investigation reveals single- to few-layered TiS2 NSs confined by N,S-doped C, suggesting the successful synthesis of the ultrathin hybrid NSs. From in vitro evaluation, the resultant product demonstrates impressive bactericidal potential against both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli bacteria, achieving a substantial decrease in the bacterial viability under a 1.2 J dose of visible-light irradiation at the lowest concentration of 5 μg·mL-1 compared to Ti3C2Tx (15 μg·mL-1), TiS2-C (10 μg·mL-1), and standard antibiotic ciprofloxacin (15 μg·mL-1), respectively. The enhanced degradation efficiency is attributed to the ultrathin TiS2 NSs encapsulated within heteroatom N,S-doped C, facilitating effective photogenerated charge-carrier separation that generates multiple reactive oxygen species (ROS) and induced physical stress as well as piercing action due to its ultrathin structure, resulting in multimechanistic cytotoxicity and damage to bacterial cells. Furthermore, the obtained results from molecular docking studies conducted via computational simulation (in silico) of the as-synthesized materials against selected proteins (β-lactamasE.coli/DNA-GyrasE.coli) are well-consistent with the in vitro antibacterial results, providing strong and consistent validation. Thus, this sophisticated study presents a simple and effective synthesis technique for the structural engineering of metal sulfide-based hybrids as functionalized synthetic bactericides.

JWA binding to NCOA4 alleviates degeneration in dopaminergic neurons through suppression of ferritinophagy in Parkinson's disease

Parkinson's disease (PD) poses a significant challenge in neurodegenerative disorders, characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). The intricate mechanisms orchestrating DA neurodegeneration in PD are not fully understood, necessitating the exploration of innovative therapeutic approaches. Recent studies have implicated ferroptosis as a major contributor to the loss of DA neurons, revealing a complex interplay between iron accumulation and neurodegeneration. However, the sophisticated nature of this process challenges the conventional belief that mere iron removal could effectively prevent DA neuronal ferroptosis. Here, we report JWA, alternatively referred to as ARL6IP5, as a negative regulator of ferroptosis, capable of ameliorating DA neuronal loss in the context of PD. In this study, synchronized expression patterns of JWA and tyrosine hydroxylase (TH) in PD patients and mice were observed, underscoring the importance of JWA for DA neuronal survival. Screening of ferroptosis-related genes unraveled the engagement of iron metabolism in the JWA-dependent inhibition of DA neuronal ferroptosis. Genetic manipulation of JWA provided compelling evidence linking its neuroprotective effects to the attenuation of NCOA4-mediated ferritinophagy. Molecular docking, co-immunoprecipitation, and immunofluorescence studies confirmed that JWA mitigated DA neuronal ferroptosis by occupying the ferritin binding site of NCOA4. Moreover, the JWA-activating compound, JAC4, demonstrated promising neuroprotective effects in cellular and animal PD models by elevating JWA expression, offering a potential avenue for neuroprotection in PD. Collectively, our work establishes JWA as a novel regulator of ferritinophagy, presenting a promising therapeutic target for addressing DA neuronal ferroptosis in PD.

Marine-Derived Cytosine Arabinoside (Ara-C) Inhibits Biofilm Formation by Inhibiting PEL Operon Proteins (Pel A and Pel B) of Pseudomonas aeruginosa: An In Silico Approach.

Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative biofilm-forming opportunistic human pathogen whose vital mechanism is biofilm formation for better survival. PelA and PelB proteins of the PEL operon are essential for bacterial-synthesized pellicle polysaccharide (PEL), which is a vital structural component of the biofilm. It helps in adherence of biofilm on the surface and maintenance of cell-to-cell interactions and with other matrix components. Here, in-silico molecular docking and simulation studies were performed against PelA and PelB using ten natural bioactive compounds, individually [podocarpic acids, ferruginol, scopadulcic acid B, pisiferic acid, metachromin A, Cytarabine (cytosine arabinoside; Ara-C), ursolic acid, oleanolic acid, maslinic acid, and betulinic acid], those have already been established as anti-infectious compounds. The results obtained from AutoDock and Glide-Schordinger stated that a marine-derived cytosine arabinoside(Ara-C) among the ten compounds binds active sites of PelA and PelB, exhibiting strong binding affinity [Trp224 (hydrogen), Ser219 (polar), Val234 (hydrophobic) for PelA; Leu365 and Glu389 (hydrogen), Gln366 (polar) for PelB] with high negative binding energy -5.518kcal/mol and -6.056kcal/mol, respectively. The molecular dynamic and simulation studies for 100ns showed the MMGBSA binding energy scores are -16.4kcal/mol (Ara-C with PelA), and -22.25kcal/mol (Ara-C with PelB). Further, ADME/T studies indicate the IC50 values of AraC are 6.10mM for PelA and 18.78mM for PelB, which is a comparatively very low dose. The zero violation of Lipinski's Rule of Five further established that Ara-C is a good candidate for drug development. Thus, Ara-C could be considered a potent anti-biofilm compound against PEL operon-dependent biofilm formation of P. aeruginosa.

CNSMolGen: A Bidirectional Recurrent Neural Network-Based Generative Model for De Novo Central Nervous System Drug Design.

Central nervous system (CNS) drugs have had a significant impact on treating a wide range of neurodegenerative and psychiatric disorders. In recent years, deep learning-based generative models have shown great potential for accelerating drug discovery and improving efficacy. However, specific applications of these techniques in CNS drug discovery have not been widely reported. In this study, we developed the CNSMolGen model, which uses a framework of bidirectional recurrent neural networks (Bi-RNNs) for de novo molecular design of CNS drugs. Results showed that the pretrained model was able to generate more than 90% of completely new molecular structures, which possessed the properties of CNS drug molecules and were synthesizable. In addition, transfer learning was performed on small data sets with specific biological activities to evaluate the potential application of the model for CNS drug optimization. Here, we used drugs against the classical CNS disease target serotonin transporter (SERT) as a fine-tuned data set and generated a focused database against the target protein. The potential biological activities of the generated molecules were verified by using the physics-based induced-fit docking study. The success of this model demonstrates its potential in CNS drug design and optimization, which provides a new impetus for future CNS drug development.

Synthesis, molecular docking study and biological evaluation of new pyrrole scaffolds as potential antitubercular agents for dual targeting of enoyl ACP reductase and dihydrofolate reductase.

In this study, new series of N'-(2-(substitutedphenoxy)acetyl)-4-(1H-pyrrol-1-yl)benzohydrazides (3a-j) 4-(2,5-dimethyl-1H-pyrrol-1-yl)-N'-(2-(substitutedphenoxy)acetyl)benzohydrazides (5a-j) were synthesized, characterized and assessed as inhibitors of enoyl ACP reductase and DHFR. Most of the compounds exhibited dual inhibition against the enzymes enoyl ACP reductase and DHFR. Several synthesized substances also demonstrated significant antibacterial and antitubercular properties. A molecular docking analysis was conducted in order to determine the potential mechanism of action of the synthesized compounds. The results indicated that there were binding interactions seen with the active sites of dihydrofolate reductase and enoyl ACP reductase. Additionally, important structural details were identified that play a critical role in sustaining the dual inhibitory activity. These findings were useful for the development of future dual inhibitors. Therefore, this study provided strong evidence that several synthesized molecules could exert their antitubercular properties at the cellular level through multi-target inhibition. By shedding light on the mechanisms through which these compounds exert their inhibitory effects, this research opens up promising avenues for the future development of dual inhibitors with enhanced antibacterial and antitubercular properties. The study's findings underscore the importance of multi-target approaches in drug design, providing a strong foundation for the design and optimization of novel compounds that can effectively target bacterial infections at the cellular level.

An efficient methodological approach for synthesis of selenopyridines: generation, reactions, anticancer activity, EGFR inhibitory activity and molecular docking studies.

In the present work, we successfully synthesized Se-alkyl selenopyridines 1 and 3, selenopheno[2,3-b]pyridine 2, and bis-selenopyridine 4 derivatives using an eco-friendly method by utilizing NaHSe instead of toxic hydrogen selenide. The effect of the temperature on the reaction was screening at various temperatures. The regiospecific reaction of selenopyridine 1 with bromine afforded an unexpected product 4,6-diamino-5-bromo-2-[(cyanomethyl)selenyl]-pyridine-3-carbonitrile (5), which was cyclized to selenopheno[2,3-b]pyridine (7) by refluxing in the presence of TEA. While its treatment with thiophenol and/or p-chlorothiophenol gave 8a, b. On the other hand, its reaction with aminothiophenol afforded 2-(benzo[d]-thiazol-2-yl)-5-bromoselenopheno[2,3-b]pyridine-3,4,6-triamine (9). Also, N-(2-cyano-4-methyl-5H-1-seleno-3,5,8-triazaacenaphthylen-7-yl)acetamide (11) and a novel series of selenoazo dyes 12a-d were synthesized by treatment of selenopheno[2,3-b]pyridine 2 with acetic anhydride and/or diazonium chlorides of aromatic amines, respectively. Then, we ascertained the potential activity of synthesized compounds against highly metastatic prostate cancer cells (PC-3) and osteosarcoma cells (MG-63) and found that 12a, 12b, 12c, and 12d were more cytotoxic than doxorubicin in both tested cell lines, showing nearly the same anticancer activity with IC50 values ranging from 2.59 ± 0.02µM to 3.93 ± 0.23µM. Mechanistically, the most potent compounds 12a and 12b proved to be potent EGFR inhibitors with IC50 values of 0.301 and 0.123µM, respectively, compared to lapatinib as a positive reference (IC50 = 0.049µM). Moreover, the docking results are in good agreement with the anticancer activity as well as the EGFR inhibitory activity, suggesting these two compounds as promising EGFR anticancer candidates.

Determination of promising inhibitors for N-SH2 domain of SHP2 tyrosine phosphatase: an in silico study.

There are many genes that produce proteins related to diseases and these proteins can be targeted with drugs as a potential therapeutic approach. Recent advancement in drug discovery techniques have created new opportunities for treating variety of diseases by targeting disease-related proteins. Structure-based drug discovery is a faster and more cost-effective approach than traditional methods. SHP2 phosphatase, encoded by the PTPN11 gene, has been the focus of much attention due to its involvement in many types of diseases. The biological function of SHP2 is enabled mostly by protein-protein interaction through its SH2 domains. In this study, we report the identification of a potential small molecule inhibitor for the N-SH2 domain of SHP2 by structure-based drug discovery approach. We utilized molecular docking studies, followed by molecular dynamics simulations and MM/PBSA calculations, to analyze compounds retrieved from the Broad's Drug Repurposing Hub and ZINC15 databases. We selected 10 hit compounds with the best docking scores from the libraries and examined their binding properties in the N-SH2 domain. We found that compound CID 60838 (Irinotecan) was the most suitable compound with a binding free energy value of - 64.45kcal/mol and significant interactions with the target residues in the domain.

Immunoinformatics assisted profiling of West Nile virus proteome to determine immunodominant epitopes for the development of next-generation multi-peptide vaccine

Emerging infectious diseases represent a significant threat to global health, with West Nile virus (WNV) being a prominent example due to its potential to cause severe neurological disorders alongside mild feverish conditions. Particularly prevalent in the continental United States, WNV has emerged as a global concern, with outbreaks indicating the urgent need for effective prophylactic measures. The current problem is that the absence of a commercial vaccine against WNV highlights a critical gap in preventive strategies against WNV. This study aims to address this gap by proposing a novel, multivalent vaccine designed using immunoinformatics approaches to elicit comprehensive humoral and cellular immune responses against WNV. The objective of the study is to provide a theoretical framework for experimental scientists to formulate of vaccine against WNV and tackle the current problem by generating an immune response inside the host. The research employs reverse vaccinology and subtractive proteomics methodologies to identify NP_041724.2 polyprotein and YP_009164950.1 truncated flavivirus polyprotein NS1 as the prime antigens. The selection process for epitopes focused on B and T-cell reactivity, antigenicity, water solubility, and non-allergenic properties, prioritizing candidates with the potential for broad immunogenicity and safety. The designed vaccine construct integrates these epitopes, connected via GPGPG linkers, and supplemented with an adjuvant with the help of another linker EAAAK, to enhance immunogenicity. Preliminary computational analyses suggest that the proposed vaccine could achieve near-universal coverage, effectively targeting approximately 99.74% of the global population, with perfect coverage in specific regions such as Sweden and Finland. Molecular docking and immune simulation studies further validate the potential efficacy of the vaccine, indicating strong binding affinity with toll-like receptor 3 (TLR-3) and promising immune response profiles, including significant antibody-mediated and cellular responses. These findings present the vaccine construct as a viable candidate for further development and testing. While the theoretical and computational results are promising, advancing from in-silico predictions to a tangible vaccine requires comprehensive laboratory validation. This next step is essential to confirm the vaccine’s efficacy and safety in eliciting an immune response against WNV. Through this study, we propose a novel approach to vaccine development against WNV and contribute to the broader field of immunoinformatics, showcasing the potential to accelerate the design of effective vaccines against emerging viral threats. The journey from hypothesis to practical solution embodies the interdisciplinary collaboration essential for modern infectious disease management and prevention strategies.

Ultrasound-assisted synthesis of novel Schiff bases from 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde and their cytotoxicity, apoptosis, cell cycle, molecular docking, and ADMET profiling

With the ultimate goal of discovering new anticancer agents, this study involved the design and synthesis of fifteen novel Schiff bases 4a,b, 5, 6a–d, 7a–e, and 8–10 which contain 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole moiety. The synthetic method depended on reaction of 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde (3) with a series of aromatic and heteroaryl amines under ultrasound irradiation to explore the influence of aromatic and heteroaryl rings on biological activity. The chemical structures of these Schiff bases were fully elucidated using various spectral and elemental analyses. The antiproliferative activities of the Schiff bases were studied by the standard SRB method. Among the new 15 Schiff bases, derivatives 4a,b, 5, and 7b have significant cytotoxic effects against PC3, HepG2, and HCT116 cancer cell lines. These four bioactive Schiff bases significantly increased the late apoptosis of all studied tumor cells. Also, both products 4a and 4b arrested the cell cycle at the G1 phase, while both compounds 5 and 7b arrested the S and G2 phases against PC3 cells. In addition, the products 4a, 4b, 5, and 7b have promising high abilities to arrest the cell cycle at the G2 phase against HepG2 and HCT116 cells. The different substitutions on the aryl ring were the basis for the structure–activity relationship study. The molecular docking study confirmed good binding interactions of these compounds with Cyclin-dependent kinase 8 (CDK-8) receptor, while the absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction supported that these bioactive products can be promising anticancer agents.

Synthesis, Activity, Toxicity, and In Silico Studies of New Antimycobacterial N-Alkyl Nitrobenzamides

Tuberculosis (TB) is a disease that plagues the frailest members of society. We have developed a family of N-alkyl nitrobenzamides that exhibit promising antitubercular activities and can be considered a structural simplification of known inhibitors of decaprenylphosphoryl-β-D-ribofuranose 2′-oxidase (DprE1), an essential Mycobacterium tuberculosis (Mtb) enzyme and an emergent antitubercular target. Hereby, we report the development of these compounds via a simple synthetic methodology as well as their stability, cytotoxicity, and antitubercular activity. Studying their in vitro activity revealed that the 3,5-dinitro and the 3-nitro-5-trifluoromethyl derivatives were the most active, and within these, the derivatives with intermediate lipophilicities presented the best activities (MIC of 16 ng/mL). Additionally, in an ex vivo macrophage model of infection, the derivatives with chain lengths of six and twelve carbon atoms presented the best results, exhibiting activity profiles comparable to isoniazid. Although the proof is not definite, the assessment of susceptibility over multiple mycobacterial species, together with the structure similarities with known inhibitors of this enzyme, support DprE1 as a likely target of action for the compounds. This idea is also reinforced by the docking studies, where the fit of our more active compounds to the DprE1 binding pocket is very similar to what was observed for known inhibitors like DNB1.

Natural lipopeptide surfactin inhibits insulin aggregation and prevents amyloid-induced cytotoxicity and inflammation

Despite the centennial of the pioneering discovery of insulin, challenges regarding insulin aggregation at the site of repeated injection, as well as during industrial production, storage, and transportation, have cast a gloom over this remarkable success story. Aggregation substantially impacts the quality, potency, and effectiveness of insulin formulation, decreasing bioavailability, intensifying the risk of immunogenicity, and endangering patient health. Herein, the suitability of Bacillus-derived amphiphilic biosurfactant surfactin was demonstrated to evade temperature-induced fibrillation of insulin. Fluorometric assessment employing thioflavin-T and intrinsic tyrosine fluorescence indicated the dose-dependent reduction in insulin unfolding and subsequent formation of fibrils. Decreased thioflavin fluorescence at the plateau stage and about a 79% increase in fibrillation lag time was observed for samples containing an equimolar ratio of insulin to surfactin. Circular dichroism analysis further indicated about a 30% increase in α-helix content in samples containing an equimolar ratio of insulin and surfactin, as compared to controls. The findings were further bolstered by dynamic light scattering, electron microscopic analysis, and native polyacrylamide gel electrophoresis. Molecular docking and simulation studies did not indicate any structural destabilization of insulin with surfactin, having major interactions at the hydrophobic and potential amyloidogenic regions of insulin B-chain: B12-B19 (VEALYLVC) and B23-B27 (GFFYT) through hydrophobic and hydrogen bonds. Notably, an almost 22% increase in cell viability was observed for cells incubated with aggregated insulin containing equimolar concentrations of SFN. Surfactin also subdued insulin amyloid-induced upregulation of the pro-inflammatory genes. Thus, surfactin may be contemplated as an additive in biopharmaceutical formulations to imbue stability and may also be evaluated as anti-amyloid therapeutics for other pathological proteinopathies.

Anxiolytic-Like and Antidepressant Effects of a 13H-indolo[2,3-a]thiopyrano[2,3-g]quinolizine Derivative

Depressive and anxiety disorders constitute some of the most prevalent mental disorders around the world. For years, the development of new lead compounds for drug discovery in this field has been an area of great attention. Recently, a series of tetrahydrocarbazole derivatives have demonstrated important anxiolytic-like activity, associated with their structures and stereochemistry. Here, we present a study of the antidepressant effect and anxiolytic-like activity of a fused thiopyrano-piperidone-tetrahydrocarboline (compound 4). The antidepressant and anxiolytic-like effects of 4 (1–50 mg/kg p.o.) were assessed with the tail suspension test and the hole-board test, respectively. This study determined the possible mechanisms involved in the anxiolytic-like actions of 4 using inhibitors or neurotransmission and evaluated its interaction with 5HT2A receptors using a molecular docking study. As an analog to the tetrahydrocarbazole core, the tetrahydrocarboline derivative showed anxiolytic-like activity (ED50 = 13 mg/kg p.o.) in the hole-board test, with a comparable effect to the reference drug, 1.5 mg/kg clonazepam, with the possible participation of the serotonergic system.

Computer-Aided Design of Novel Active Components in Plant Protection

The production demands highly specific environmentally and toxicologically acceptable plant protection products are increasing. Computer-aided molecular design of new active components has a great deal in developing plant protection products to avoid that long-lasting and expensive process. Computational design of future compounds and their synthesis, evaluation of their effectiveness on harmful and beneficial organisms in the soil, as well as detailed research mechanism of action at the molecular level, represents an initial stage in the long-lasting and expensive process of plant protection products. In this paper, the recent advances in quantitative structure-activity relationship (QSAR) studies, molecular docking, and calculation of “Pesticidelikeness properties “, as well, have been reviewed. QSAR models for antifungal activities against phytopathological fungi were obtained for the thiazoline and coumarine derivatives, coumarinyl Schiff bases, and coumarin-1,2,4-triazoles. A molecular docking study revealed that antifungal activities of fluorinated pyrazole aldehydes are related to the inhibition of proteinase K, coumarinyl Schiff bases with endoglucanase and pectinase, hybrids of coumarins and 1,2,4-triazoles with sterol 14α-demethylase inhibition, 3-gydroxycoumarin chitin synthase, while γ-thionins strongly binds to fungal membrane moieties.

Simultaneous Exposure to Noise and Toluene Induces Oxidative and Inflammatory Damage in the Heart of Wistar Rats: Therapeutic Potential of Olea europaea L. Leaf Extract

Simultaneous Exposure to Noise and Toluene Induces Oxidative and Inflammatory Damage in the Heart of Wistar Rats: Therapeutic Potential of Olea europaea L. Leaf Extract

Proposed prototype for a quantitative biosensor for insulin detection using a liquid crystal

In this paper, we present a novel approach for label-free detection of human insulin using 5CB liquid crystal (LC). Monitoring insulin levels in the body is essential for treating diseases like diabetes, which are caused by insufficient production or inefficient use of insulin. Contemporary techniques of detection rely on glucose detection, and limited information is available on the direct detection of insulin. A simple method using a common room temperature LC 4-cyano-4-pentyl biphenyl (5CB) interacting with different concentrations of insulin, observed through a polarising optical microscope (POM), is reported in this paper. An analysis of observed textures revealed the detection of insulin as low as 25 μM concentration. The distinguishable features of the observed textures provide a scale for estimating insulin concentration. The effect of different pH and salt concentrations was studied in order to understand the optimal working condition of the proposed biosensor. Image J analysis demonstrated a positive correlation (R2 equal to 0.9553) between grey index (GI) values and human insulin concentrations. RGB analysis and interference studies confirmed the biosensor’s specificity in insulin detection. To correlate the textures to the happenings at the molecular level, docking studies were carried out. In addition to this, properties such as aromaticity, H-bond, hydrophobicity, interpolated charges, ionizability and solvent accessible area (SAS) in the minimum energy binding sites of 5CB-LC and human insulin chains were measured to know more about the interaction properties. This novel strategy shows promise for improving insulin detection sensitivity and accuracy, ultimately leading to better diabetes management and healthcare outcomes.

Probing Alzheimer's pathology: Exploring the next generation of FDDNP analogues for amyloid β detection

Fluorescent probes are a powerful tool for imaging amyloid β (Aβ) plaques, the hallmark of Alzheimer’s disease (AD). Herein, we report the synthesis and comprehensive characterization of 21 novel probes as well as their optical properties and binding affinities to Aβ fibrils. One of these dyes, 1Ae, exhibited several improvements over FDDNP, an established biomarker for Aβ- and Tau-aggregates. First, 1Ae had large Stokes shifts (138–213 nm) in various solvents, thereby reducing self-absorption. With a high quantum yield ratio (φ(dichloromethane/methanol) = 104), 1Ae also ensures minimal background emission in aqueous environments and high sensitivity. In addition, compound 1Ae exhibited low micromolar binding affinity to Aβ fibrils in vitro (Kd = 1.603 µM), while increasing fluorescence emission (106-fold) compared to emission in buffer alone. Importantly, the selective binding of 1Ae to Aβ1–42 fibrils was confirmed by an in cellulo assay, supported by ex vivo fluorescence microscopy of 1Ae on postmortem AD brain sections, allowing unequivocal identification of Aβ plaques. The intermolecular interactions of fluorophores with Aβ were elucidated by docking studies and molecular dynamics simulations. Density functional theory calculations revealed the unique photophysics of these rod-shaped fluorophores, with a twisted intramolecular charge transfer (TICT) excited state. These results provide valuable insights into the future application of such probes as potential diagnostic tools for AD in vitro and ex vivo such as determination of Aβ1–42 in cerebrospinal fluid or blood.

Theoretical spectroscopic electronic elucidation with polar and non-polar solvents (IEFPCM model), molecular docking and molecular dynamic studies on bendiocarb -antiallergic drug agent

The potential antiallergic compound bendiocarb was studied theoretically by polar and non-polar (six) solvents (IEFPCM model) by quantum chemical DFT calculations. Rotational potential barriers were estimated for water, acetone, THF, chloroform, benzene, and toluene are 12.62, 12.45, 12.55, 12.69, 12.74 and 12.57 kJ/mol. Analysis was done on the variations in geometries brought about by the electronegative atom’s replacement as well as the intramolecular interactions caused by the benzodioxol ring. NBO analysis as well as geometrical equilibrium have been performed using DFT employing the B3LYP technique with the 6-311G++(d, p) basis set. In vibrational analysis, CH stretching of bendiocarb was theoretically estimated within 3207–3181 cm−1 (gas), 3207–3184 cm−1 (acetone and water), 3207–3182 cm−1 (benzene and toluene), and 3207–3183 cm−1 (chloroform and THF) due to CN vibrations is challenging because of the overlapping and appearance of multiple bands in similar regions. Energy gaps for Bendiocarb in different solvents for water (5.719 eV), acetone (5.716 eV), THF (5.722 eV), chloroform (5.724 eV), benzene (5.731 eV), toluene (5.730 eV), and gas phase (5.746 eV). Lipinski’s rule of five was exploited to guide research on drug similarity and oral action. Using docking simulation against the antiallergic protein, a binding energy of −5.22 kcal/mol, 4P5M has been examined. The protein 4P5M exhibits variations between 0.12 and 0.155 nm for RMSD in molecular dynamic simulation. One can infer information about the pharmacokinetic features of the target molecule from its drug similarity, absorption, distribution, metabolism, excretion, and toxicity properties.