In-silico Studies Research Articles

Novel triterpenoid, Schidigeragenin B resourced from the mother tincture of Conium maculatum: A promising future Antidiabetic drug

As of 2021, an estimated 537 million people had diabetes worldwide, accounting for 10.5 % of the adult population, with type 2 making up about 90 % of all cases. The common antidiabetic drugs have several problems like hypoglycemia, skin rash and itching, weight gain, kidney complications, etc. So, there is a need to explore safer alternative medications from natural sources. This study examines the antidiabetic potential and metabolomic profiling of Conium maculatum, a homeopathic medicine prescribed for diabetic patients. Potent DPPH scavenging of the sample was observed with an IC50 value of 75.05 ± 6.33 μg/mL. α-Amylase and α-glucosidase enzyme inhibition by the mother tincture of Conium maculatum was evaluated through in-vitro studies, highlighting effective antidiabetic activity with IC50 values of 86.53±1.76 μg/mL and 124±7.903 μg/mL, respectively. Metabolomic profiling of the mother tincture of Conium maculatum was done by LC-MS/MS to identify a total of 47 phyto-compounds that were subjected to ADMET profiling, followed by in-silico docking and MDS with target receptors associated with diabetes. Six compounds were short-listed for in-silico docking studies with five target proteins, α-amylase, α-glucosidase, GLUT-4, GLP-1, and IRS1. Three compounds, Schidigeragenin B, 10-oxo-11-octadecen-13-olide, and Distichonic acid A, showed strong binding affinities to these protein receptors, crucial for diabetes remediation. Among these compounds, Schidigeragenin B, a novel triterpenoid shows the strongest binding affinities towards these receptors, and the ADMET properties highlighted its drug likeness. Conclusively, the present study identified Schidigeragenin B, resourced from the mother tincture of Conium maculatum, as the potent bioactive antidiabetic molecule for combating diabetes.

Larvicidal activity of β-Citral: An In-vitro and In-silico study to understand its potential against mosquito

Tropical and subtropical regions face millions of deaths from mosquito-borne illnesses yearly. Insecticides prevent transmission but pose health risks like dermatitis and allergies. The primary objective was to mitigate the recurring dependence on synthetic insecticides, thereby curbing the development of mosquito resistance. Leaves of Cymbopogon flexuosus (lemongrass) was collected from Mayurbhanj, India, processed, then extracted by steam distillation for essential oils & analyzed spectroscopically. Larvicidal assays were performed across varying concentrations, revealing the significant mortality induced by the Cymbopogon flexuosus extract against Anopheles stephensi larvae. 3D structure was modelled by using G protein-coupled receptors (GPCR) sequence and structural stability was also validated. After docking the binding free energy was determined from GPCR protein with β-citral complex. Molecular dynamics (MD) study was conducted on the docked pose that displayed an optimal interactome profile. The larvicidal assay at the 12th and 24th hour revealed the highest LC50 (lethal concentration) of 23.493 ppm and 19.664 ppm . β-Citral has a high binding affinity and an identifiable binding site, which suggests that it may play a larvicidal role in regulating the receptor's function by creating stable complexes with it. β-Citral from lemongrass oils has potential larvicidal activity and effective against GPCR family 1 of mosquito and highly effective repellents against mosquito-borne diseases.

Lattice Boltzmann Model Investigation of Simultaneous Imbibition/Evaporation in PEMFC Cathodic Catalyst Layer Using Reconstructed 3D Image Data from Transmission Electron Microscopy

Proton Exchange Membrane Fuel Cells (PEMFCs) are widely used and significant attention is directed towards optimizing of the cathode catalyst layer. The critical focus revolves around refining the multi-phase boundary of the electrically conducting carbon support, the ion-conducting ionomer, the catalyst particles as well as the pore space that can be either occupied by oxygen (feedstock) or water (product). Challenges related to mass transport limitations of oxygen towards these multiple-phase boundaries, also denoted as active sites, persist, especially when liquid water increasingly saturates the pore space (Fig. 1). Furthermore, the evaporated water additionally hinders oxygen transport in the gas phase1,2. This study focuses on the investigation of pore-scale transport mechanisms inside of the cathodic catalyst layer, taking into account the counter-current diffusion of oxygen and water vapor in the gas phase as well as the generation of liquid water that increasingly saturates the void space. For this purpose, a multi-phase and multi-component pore scale Lattice Boltzmann model (LBM), coupled to two-phase reaction, was implemented. The LBM is tailored based on previous works3,4, including the localized generation of water at constant current densities, the imbibition of the pore structure with water counter-currently to the diffusion of oxygen, and the simultaneous evaporation of water. An actual 3D cathode catalyst layer from a commercial membrane electrode assembly, reconstructed from transmission electron microscopy (TEM) image data, was employed. It was imaged using a source voltage of 200kV and a current of 2 nA. The scanned sample had an approximate total volume of 500 × 500 × 100 nm3. From this, a 3D domain of 138 × 138 × 58 nm3 was reconstructed for this study. A 2D cross-section of the reconstructed image is exemplarily shown in Fig. 1. The in-silico study of water and oxygen transport through the catalyst layer elaborates the relationship between the rates of water invasion and evaporation in dependence of current density and catalyst layer structure. The critical conditions for water flooding are evaluated for different process conditions. Fig. 1 Schematic representation of the cathode catalyst layer: The ionomer is represented in white; the carbon for electron connectivity is represented in gray; pore space for oxygen and water transport in yellow; the black circles represent the active sites, i.e., Pt-particles located at the multi-phase boundary of ionomer, carbon and oxygen-filled pores; the red circles represent the inactive sites, that have no connection to ion and/or oxygen transport pathways. References A. Suzuki et al., Int. J. Hydrogen Energy, 36, 2221–2229 (2011) https://www.sciencedirect.com/science/article/pii/S0360319910022913.M. El Hannach, M. Prat, and J. Pauchet, Int. J. Hydrogen Energy, 37, 18996–19006 (2012) https://www.sciencedirect.com/science/article/pii/S0360319912022069.S. Bhaskaran et al., Dry. Technol., 40, 735–747 (2022) https://doi.org/10.1080/07373937.2021.1898417.S. Bhaskaran et al., Int. J. Hydrogen Energy, 47, 31551–31565 (2022) https://www.sciencedirect.com/science/article/pii/S0360319922030932. Figure 1

Resolution limits for radiation-induced acoustic imaging for in vivo radiation dosimetry

Objective. Radiation-induced acoustic (RA) computed tomographic (RACT) imaging is being thoroughly explored for radiation dosimetry. It is essential to understand how key machine parameters like beam pulse, size, and energy deposition affect image quality in RACT. We investigate the intricate interplay of these parameters and how these factors influence dose map resolution in RACT. Approach. We first conduct an analytical assessment of time-domain RA signals and their corresponding frequency spectra for certain testcases, and computationally validate these analyses. Subsequently, we simulated a series of x-ray-based RACT (XACT) experiments and compared the simulations with experimental measurements. In-silico reconstruction studies have also been conducted to demonstrate the resolution limits imposed by the temporal pulse profiles on RACT. XACT experiments were performed using clinical machines and the reconstructions were analyzed for resolution capabilities. Main results. Our paper establishes the theory for predicting the time- and frequency-domain behavior of RA signals. We illustrate that the frequency content of RA signal is not solely dependent on the spatial energy deposition characteristics but also on the temporal features of radiation. The same spatial energy deposition through a Gaussian pulse and a rectangular pulse of equal pulsewidths results in different frequency spectra of the RA signals. RA signals corresponding to the rectangular pulse exhibit more high-frequency content than their Gaussian pulse counterparts and hence provide better resolution in the reconstructions. XACT experiments with ∼3.2 us and ∼4 us rectangular radiation pulses were performed, and the reconstruction results were found to correlate well with the in-silico results. Significance. Here, we discuss the inherent resolution limits for RACT-based radiation dosimetric systems. While our study is relevant to the broader community engaged in research on photoacoustics, x-ray-acoustics, and proto/ionoacoustics, it holds particular significance for medical physics researchers aiming to set up RACT for dosimetry and radiography using clinical radiation machines.

Evaluation of anti-diabetic, anti-oxidant and anti-bacterial activities of essential oil collected from wildly growing Calotropis gigantea (Linn.) Aiton f. and its therapeutic applications: insights from chemical profiling, in-vitro and in-silico studies

Calotropis gigantea, often known as giant milkweed, the plant is widely known for producing herbal essential oils that are used as traditional and complementary medicine to cure various ailments. The aim of the present study was evaluation of anti-diabetic, anti-oxidant and anti-bacterial activities of essential oil collected from wildly growing Calotropis gigantea and its its therapeutic applications via chemical profiling, in-vitro and in-silico studies. After Calotropis gigantea (CEO) essential oil was extracted by hydro-distillation, its phytochemical, antioxidant, antibacterial, and anti-diabetic properties were assessed. Fingerprint analysis and GC-FID were used to create a chemical profile. Various tests for antioxidants, such as DPPH, nitric oxide radical, and iron chelating activity, were conducted. The disk diffusion approach was used for antibacterial efficacy against Gram-negative (G-) bacteria. The test of α-amylase inhibition was utilized to investigate anti-diabetic efficacy. In-silico analysis was also conducted to find out interaction of some components to α-amylase enzyme. Chemical profiling indicated the presence of phytol (24%), stearic acid (10%), and cyclohexyl ketone (6%), as predominant components. There was notable antioxidant activity ranged from 82 to 97% for various assays. IC50 values for various assays were iron chelating activity: 18.610, DPPH scavenging activity: 28.246, nitric oxide radical scavenging activity: 58.113. CEO showed a zone of inhibition value of 0.5 cm and significant antibacterial activity against Gram-negative (G-) bacteria. CEO blocked α-amylase in dose-dependent way. At a higher amount of 250 µl, CEO inhibition was 63% and mode of inhibition un-competitive. In-silico analysis validated the blocking of α-amylase and interaction of phytocomponents to α-amylase enzyme which were further validated by UV and fluorescent quenching techniques. It was determined that CEO may be extensively used in many different industries, including as food, herbal medicine, cosmetics.

Synthesis of quercetin derivatives as cytotoxic against breast cancer MCF-7 cell line invitro and insilico studies.

Background: Quercetin being antioxidant and antiproliferative agent acts by inhibiting CDK2, with an increase in cancer prevalence there is a need to profile quercetin derivatives as CDK2 inhibitors.Materials & method: Schiff bases of quercetin were synthesized as cytotoxic agents against the MCF7 cell line. FTIR, 1H-NMR and 13C-NMR, CHNS/O analysis were employed along with invivo and insilico activities.Results & conclusion: 2q, 4q, 8q and 9q derivatives have maximum cytotoxic effect with IC50 values 39.7±0.7, 36.65±0.25, 35.49±0.21 and 36.99±0.45, respectively. Molecular docking also confirmed these results 8q has the highest binding potential of -9.165KJ/mole making it a potent inhibitor of CDK2. These derivatives can be used as lead compounds as potent CDK2 inhibitors.

Deciphering the genetic impact of signal peptide missense CTLA-4 polymorphism with rheumatoid arthritis in the Indian population: A case-control and in silico studies

Cytoplasmic T Lymphocyte Antigen-4 (CTLA-4) gene encodes for a glycoprotein, expressed on activated T-cells to transfer an inhibitory signal to control T-cell activation and proliferation. Techniques coupled with Real-time Polymerase Chain Reaction (PCR) and High-Resolution Melting Analysis (HRMA) were used to screen a missense signal peptide polymorphism (CTLA-4 + 49 A/G rs231775) in the Indian population to detect its association with Rheumatoid Arthritis (RA). Further, the resulting outcome was confirmed by Sanger’s sequencing technique, and genotype frequencies were calculated. In eukaryotic cells, the M domain of the Signal Recognition Particle (SRP-54) recognizes the N-terminal region of the Signal Peptide (SP) sequence. SP directs the polypeptide chain into the Sec-61 translocon of the Endoplasmic Reticulum (ER) for further protein modification. As the Single Nucleotide Polymorphism (SNP) rs231775 lies in the signal peptide region of CTLA-4, an in-silico study was also performed to predict the mRNA stability and SP-SRP protein interaction. From the study, it was observed that the genotype frequency of rs231775 SNP G/G homozygous dominant was significantly higher in RA patients than G/A heterozygous dominant and A/A homozygous recessive conditions (Odd Ratio (OR) = 2.0862; 95 % Confidence Interval (C.I) = 1.2584 to 3.4584; Relative Risk (RR) = 1.8507; p = 0.0044). Moreover, the rs231775 SNP G allele frequency was higher in RA than the control group G = 0.407 (40.7 %) vs 0.32 (32 %). In silico approaches of Protein-Protein docking and Molecular Dynamics (MD) simulation reveal CTLA-4 rs231775 SNP (G allele) has destabilized the SP-SRP protein complex, which may affect the translocation of CTLA-4 nascent polypeptide chains into the ER via activating Regulation of Aberrant Protein Production (RAPP) pathway.

Phytochemicals for Breast Cancer Therapeutic Intervention: Exploratory In-Silico Molecular Docking Study

Phytochemicals for Breast Cancer Therapeutic Intervention: Exploratory In-Silico Molecular Docking Study

Exploring the geographical variability of Asphaltum punjabianum (Shilajit) from India in elements and phytochemicals variations using GC–MS/MS, LC, ICP OES, and in-silico studies

Shilajit is an ancient herbal medicine from India with many uses. It is a viscous material prominently present in the Himalayan and Hindukush rocks of the Indian region. The formation due to plant decompostion with time. Herbs assosciated to the stones reveals about composition of Shilajit. Primary objective is to create GCMS/MS and LC-analysis techniques for separating the phytochemicals and complete profiling of volatile and non-volatile metabolites found in Shilajit. Accordingly, an attempt was undertaken to develop a method for standardisation and, subsequently, certification inorganic content and purity of shilajit in various indian regions S-01, S-02, S-03, S-04, and S-05. Thus, an effort was made to create a fundamental technique for standardization and, consequently, authentication of shilajit that was acquired from various geographical locations.Trace metal concentrations were measured using ICP OES in mg Kg−1 for each sample. These elements included As, Pb, Cd, Ag, Al, B, Ba, Cr, Cu, Fe, Mn, Ni, Sb, Se, Zn, P, Ca, K, Mg, and Na. ICP OES analysis observed the significant concentration of Ca and K, in S-01 (102631 and 26779), S-02 (13529.25 and 36866.35), S-03 (8170.84 and 37989.10), S-04 (9616.37 and 18843.77), and S-05 (4992.10 and 2120.64), appropriately. By measuring the DPPH radical scavenging activity were assessed for their antioxidant activities of the S-01, S-02, S-03, S-04, and S-05 samples: 12.316 ± 0.561 %, 13.144 ± 2.884 %, 15.105 ± 1.421 %, 19.683 ± 2.013 %, and 0.0724 ± 1.045 %, respectively. Concurrently, TPC studies on Shilajit found between 10 and 150 mg g−1 wt Similarly, shilajit’s TFC was analysed with geographically. TFC were found in mg QCE/g of wt of S-01 12.56, S-02 5.56, S-03.48, S-04 49.23, and S-05 5809 each respectively. The phytochemicals protocatechuic acid and hippuric were tested for in silico anti-inflammatory and antihyperglycemic activity of acid, which need to be explored in-vivo applications.

In-silico Studies of Jatropha curcas Bioactive Compounds as Anti SARS-CoV-2

In-silico Studies of Jatropha curcas Bioactive Compounds as Anti SARS-CoV-2

Synthesis and in-silico Studies of 4-phenyl thiazol-2-amine Derivatives as Putative Anti-breast Cancer Agents.

Breast cancer (BC) is the second-leading cause of cancer-related fatalities in women after lung cancer worldwide. The development of BC is significantly influenced by estrogen receptors (ERs). The problem with current cancer treatments is selectivity, target specificity, cytotoxicity, and developing resistance. Thiazole scaffolds are gaining popularity in drug discovery due to their broad range of biological activity. It has the extraordinary capacity to control a variety of cellular pathways, and its potential for selective anticancer activity can be explored. Synthesis and in-silico</i> studies of 4-Phenyl thiazol-2-amine derivatives as anti-breast cancer agents and molecular docking was used to assess the compounds' capacity to bind ER-α protein target. In this study, 4-Phenylthiazol-2-amine derivatives (3a-j) have been synthesized, and using Schrodinger software, molecular docking and ADME studies of the compounds were conducted. Most of the synthesized compounds have shown dock scores ranging from -6.658 to - 8.911 kcal/mol, which is better than the standard drug tamoxifen (-6.821 kcal/mol). According to molecular docking, all compounds fit in the protein's active site and have the same hydrophobic pocket as the standard drug tamoxifen. Further, all of the compounds' ADME properties are below acceptable limits. Compound 3e showed the best docking score of -8.911. All compounds' ADME properties are within acceptable limits, and their p/o coefficients fall within a range, suggesting they will all have sufficient absorption at the site of action. These compounds can be evaluated invitro</i> and in-vivo</i> in the future.

Exploration of thiosemicarbazone-quinolone hybrids over in-silico, antioxidant, and zebrafish embryo toxicity studies

In this study, we successfully synthesized a series of acetyl quinolone thiosemicarbazones (5a-d, 6a-d) using a simple work-up procedure yielding column-free products. The structures of the synthesized compounds were confirmed by various spectroscopic techniques, including 1H, 13C, and 2D NMR, along with FT-IR. Detailed 2D NMR analyses such as COSY, HSQC, and HMBC were also performed. The biological activities were evaluated through in-vitro, in-vivo, and in-silico studies. In-vitro antioxidant properties were assessed using radical scavenging assays, revealing significant activity for compounds 5b and 6b, likely due to the aromatic ring substitution in the thiosemicarbazide side chain. In-vivo zebrafish embryo toxicity studies indicated minimal toxicity for these compounds. Additionally, in-silico studies showed that compounds 5b and 6b have good binding energies for proteins 2C0U, 3NM8 and 2X08. Further the DFT study of HOMO and LUMO energy gap is small for 5b and 6b. These findings suggest that acetyl quinolone thiosemicarbazones are promising candidates for various biological applications due to their potent antioxidant activity and low toxicity.

Phytochemical, antioxidant, and in-silico studies of Erigeron sumatrensis from Gayo Highlands as a potential inhibitor of Type-2 diabetes mellitus

Abstract. Puspa VR, Zumaidar, Nurdin, Fitmawati. 2024. Phytochemical, antioxidant, and in-silico studies of Erigeron sumatrensis from Gayo Highlands as a potential inhibitor of type-2 diabetes mellitus. Biodiversitas 25: 3179-3192. Erigeron sumatrensis Retz., a wild medicinal herb, was determined qualitatively and quantitatively for its leaf extract's phytochemical constituents and antioxidant capacity and to conduct computational studies. Secondary metabolites identified included flavonoids, phenolics, terpenoids, steroids, and alkaloids. The methanol fraction exhibited the greatest TPC (5945.45 mg GAE/g). Antioxidant activity, as determined by the ABTS assay, indicated a significant radical scavenging activity in the methanol fraction of E. sumatrensis leaves, with an IC50 value of 57.67 ?g/mL. In silico molecular docking revealed that cucurbitacin b, 25-desacetoxy-?-sitosterol, and ?-amyrin exhibited potential as ?-glucosidase inhibitors (PDB ID: 2QMJ). The same compounds demonstrated inhibitory properties against ?-amylase (PDB ID: 2QV4), with acarbose as a positive control with a binding energy of -7.8 kcal/mol. The ADMET profiles indicated compliance with Lipinski's rule of five for all compounds, suggesting their suitability as an orally administered drug. Based on these findings, E. sumatrensis has excellent potential as a source of raw materials for antidiabetic drug formulation, so it needs to be further investigated for pharmaceutical applications.

Identification of a novel mutation of the FLT3 gene located on the juxtamembrane domain from acute myeloid leukemia patients.

FLT3 gene mutations are genetic abnormality that caused leukemogenesis. Furthermore, presence of FLT3 mutations is associated with poor prognosis in AML. This study aimed to identify FLT3 gene mutations so that it can be used as a genetic reference for the AML patients in Indonesian population. This cross-sectional study recruited 63 AML de novo patients between August 2021 and July 2023 at Cipto Mangukusumo General Hospital and Dharmais Cancer Hospital. We collected peripheral blood from the patients for DNA isolation. FLT3 gene mutation was detected using PCR method, then followed by the Sanger sequencing. Novel mutation in exon-14 continued to in silico study using SWISS MODEL server for modelling protein and PyMOL2 software for visualizing the protein model. Frequency FLT3-ITD mutation was 22% and 6 (10%) patients had a novel mutation on juxtamembrane domain. The number of FLT3-ITD insertions was 24bp to 111bp, with a median of 72bp. Novel mutation indicated a change in the protein sequence at amino acid number 572 from Tyrosine to Valine and formed a stop codon (UGA) at amino acid position ins572G573. In-silico study from novel mutation showed the receptor FLT3 protein was a loss of most of the juxtamembrane domain and the entire kinase domain. A novel FLT3 gene mutation was found in this study in the juxtamembrane domain. Based on the sequencing analysis and in silico studies, this mutation is likely to affect the activity of the FLT3 receptor. Therefore, further studies on this novel mutation are needed.

A natural compound from plant, Thailandiol as a potential dual inhibitor for spike glycoprotein, and RBD region of ACE2-spike glycoprotein: an insilico ADMET analysis and molecular docking study

COVID-19 primarily targets the angiotensin-converting enzyme 2 (ACE2) receptor, which enables the virus to infiltrate host cells via the spike glycoprotein. In this research, Thailandiol could serve as a dual inhibitor for the spike glycoprotein and the interface of the spike glycoprotein and ACE2. This was achieved using molecular docking and ADMET analysis. We docked Thailandiol against the crystal structures of the spike glycoprotein and the Receptor Binding Domain region of SARS-CoV-2 and the ACE2 receptor using AutoDock4 & Vina. Thailandiol demonstrated high binding affinity and favourable interactions with both the spike glycoprotein and the RBD region. Additionally, Thailandiol exhibited favourable ADMET properties and Swiss target prediction. Our in-silico research indicates that Thailandiol has the potential to be a dual inhibitor for the spike glycoprotein and the interface of the RBD region, and could be developed into a novel therapeutic agent for COVID-19.

In-silico study unveils potential phytocompounds in Andrographis paniculata against E6 protein of the high-risk HPV-16 subtype for cervical cancer therapy

Despite therapeutic advancements, cervical cancer caused by high-risk subtypes of the human papillomavirus (HPV) remains a leading cause of cancer-related deaths among women worldwide. This study aimed to discover potential drug candidates from the Asian medicinal plant Andrographis paniculata, demonstrating efficacy against the E6 protein of high-risk HPV-16 subtype through an in-silico computational approach. The 3D structures of 32 compounds (selected from 42) derived from A. paniculata, exhibiting higher binding affinity, were obtained from the PubChem database. These structures underwent subsequent analysis and screening based on criteria including binding energy, molecular docking, drug likeness and toxicity prediction using computational techniques. Considering the spectrometry, pharmacokinetic properties, docking results, drug likeliness, and toxicological effects, five compounds—stigmasterol, 1H-Indole-3-carboxylic acid, 5-methoxy-, methyl ester (AP7), andrographolide, apigenin and wogonin—were selected as the potential inhibitors against the E6 protein of HPV-16. We also performed 200 ns molecular dynamics simulations of the compounds to analyze their stability and interactions as protein–ligand complexes using imiquimod (CID-57469) as a control. Screened compounds showed favorable characteristics, including stable root mean square deviation values, minimal root mean square fluctuations and consistent radius of gyration values. Intermolecular interactions, such as hydrogen bonds and hydrophobic contacts, were sustained throughout the simulations. The compounds displayed potential affinity, as indicated by negative binding free energy values. Overall, findings of this study suggest that the selected compounds have the potential to act as inhibitors against the E6 protein of HPV-16, offering promising prospects for the treatment and management of CC.

Synthesis and molecular structure exploration of novel piperidin-4-one imine derivatives combined with DFT and X-ray: A new class of antioxidant and anti-inflammatory agents

Inflammation is one of the pertinent responses of the body, depending mainly on the process and factors involved in combating the oxidative species produced either by any infection or failure of the antioxidant pathways. In search of new compounds to exhibit antioxidant and anti-inflammatory activity here, we have successfully reported the synthesis of three novel compounds of Piperidin-4-one skeleton by adopting simple and convenient methods. Compound 1, (3, 3-dimethyl-2, 6-bis(3,4,5-trimethoxyphenyl) piperidin-4-one) was synthesized by one-pot Mannich condensation reaction having good yield (88 %). Furthermore in the next step highly functionalized imine derivatives, Compound 2 (3,3-dimethyl-2,6-bis (3,4,5-trimethoxyphenyl) piperidine-4-one) hydrazine carbothioamide) and Compound 3 (3,3-dimethyl-2,6-bis(3,4,5-trimethoxyphenyl) piperidin-4-one oxime) were prepared by the condensation reaction with thiosemicarbazide and hydroxylamine hydrochloride with compound 1, respectively. The structure of the compounds has been deduced by the combined use of modern spectroscopic and single crystal x-ray diffraction (XRD) techniques. in-silico ADMET studies predict pharmacokinetic properties and showed that compounds are non toxic on vital organs. The optimized geometry and reactivity parameters of compounds were further calculated based on the B3LYP/6-31G (d, p) density functional theory (DFT). The negative values of chemical potential follow the trend as 2 (−0.2101) >3 (−0.2198) >1(-0.2233) signifies that all compounds are reactive in nature as evident from in-vitro antioxidant and anti-inflammatory response were determined by using the DDPH assay and protein denaturation methods respectively. Compounds possess good radical scavenging activity having IC 50 values 30.392 μM (2), 37.802 (1) μM, and 72.285 (3) μM, and anti-inflammatory response in same manner indicating that 2 (71.3 %) is more active than compound 1 (43.5 %) and 3 (39.3 %) marking them as a potential antioxidant and anti-inflammatory agents.

In-silico study of the impact of system design parameters on microcalcification detection in wide-angle digital breast tomosynthesis.

Accurate detection of microcalcifications ( ) is crucial for the early detection of breast cancer. Some clinical studies have indicated that digital breast tomosynthesis (DBT) systems with a wide angular range have inferior detectability compared with those with a narrow angular range. This study aims to (1)provide guidance for optimizing wide-angle (WA) DBT for improving detectability and (2)prioritize key optimization factors. An in-silico DBT pipeline was constructed to evaluate detectability of a WA DBT system under various imaging conditions: focal spot motion (FSM), angular dose distribution (ADS), detector pixel pitch, and detector electronic noise (EN). Images were simulated using a digital anthropomorphic breast phantom inserted with clusters. Evaluation metrics included the signal-to-noise ratio (SNR) of the filtered channel observer and the area under the receiver operator curve (AUC) of multiple-reader multiple-case analysis. Results showed that FSM degraded sharpness and decreased the SNR and AUC by 5.2% and 1.8%, respectively. Non-uniform ADS increased the SNR by 62.8% and the AUC by 10.2% for filtered backprojection reconstruction with a typical clinical filter setting. When EN decreased from 2000 to 200 electrons, the SNR and AUC increased by 21.6% and 5.0%, respectively. Decreasing the detector pixel pitch from 85 to improved the SNR and AUC by 55.6% and 7.5%, respectively. The combined improvement of a pixel pitch and EN200 was 89.2% in the SNR and 12.8% in the AUC. Based on the magnitude of impact, the priority for enhancing detectability in WA DBT is as follows: (1)utilizing detectors with a small pixel pitch and low EN level, (2)allocating a higher dose to central projections, and (3)reducing FSM. The results from this study can potentially provide guidance for DBT system optimization in the future.

Targeting inflammation through inhibition of COX-2 by substituted 4-thiazolidinone analogues: in-vitro, in-vivo and in-silico studies

The prolonged or chronic use of anti-inflammatory agents that are being used clinically is highly unsafe. This flaw or disadvantage has motivated scientists to create new heterocyclic compounds with minimal toxicity and possible anti-inflammatory effects. The design and synthesis of ten 4-thiazolidinone containing pyridine derivatives are reported in the current study article. After conducting an in vitro study, it was discovered that they had anti-inflammatory potential. The compounds were analysed for the COX-2 inhibitory activity. VSA6 found to be most potent candidate, screened further. Also. VSA6 emerged as most potent inhibitor against COX-2 with IC50 of 17.32±1.06µM. Further the antioxidant potential of the candidates was analysed in-vitro data suggested that, synthesized compounds showed the anti-oxidant activity with VSA6, and VSA10 being remarkably potent compounds with IC50 values of 34.39 and 37.32 µM respectively. In RAW 264.7 cells, VSA6 demonstrated dose-dependent suppression of mitochondrial superoxide generation at concentrations of 10 and 20 µM. It decreased intracellular expression of the LPS induced reactive oxygen species; mitochondria induced superoxide, MAPK7 and NF-κβ. The molecule also diminished the expression of extracellular of TNF-α, IL-6, MAPK7, NF-κβ and COX-2 and enhanced the expression of anti-oxidant enzymes i.e. GSH and SOD2. To further validate the COX-2 inhibitory activity of VSA6, gene and protein level expression study was conducted; VSA6 decreased the LPS induced COX-2 expression analysed by flow cytometer, immunofluorescence assay and RT-qPCR. The most efficient compound showed encouraging anti-inflammatory action when tested for in vivo anti-inflammatory potential in carrageenan induced model. To find out how this developed compound interacted with COX-2, an anti-inflammatory target, molecular docking analysis was used. According to the findings, the majority of the compounds could make good candidates for the creation of brand-new anti-inflammatory drugs.

In-silico molecular docking, ADME study, and molecular dynamic simulation of new azetidin-2-one derivatives with antiproliferative activity

Over the past two decades, protein kinase has been a heavily studied target in the development of new anti-proliferative medications. Heterocyclic systems have been identified as the preferred scaffold because of their wide range of biological properties. In this research, the objective was to design and develop fifteen novel azetidin-2-one derivatives and assess their cytotoxic potential as inhibitors of the epidermal growth factor receptor, which is considered one of the key factors influencing cell growth and proliferation. The crystal structure of inactive EGFR tyrosine kinase domain ligand erlotinib from protein data bank was retrieved in order to be docked with our proposed azetidine-2-one derivatives to evaluate their activity as anti-proliferative agents. In this article, an in-silico molecular docking approach proposes that these azetidine-2-one derivatives have satisfactory binding contact with the erlotinib binding site. Although, three compounds have been identified as the most powerful as they have PLP fitness scores of (77.79, 76.68 and 71.46), respectively, while the reference ligand’s fitness score was (71.94). Additionally, all of our derivatives have satisfied the Swiss-ADME parameters, indicating that they may be orally active compounds. In conclusion, two compounds (A-2 and A-8) have better PLP fitness, and one (A-14) has a comparable score in comparison to the reference ligand, at the active site of epidermal growth factor receptor. indicating that the novel azetidine-2-one derivatives have shown interesting results and could be used as model compounds to create novel anti-proliferative drugs. However, more pharmacological evaluation is needed.