Evaluation of Anti-Hyperlipidemic Activity of the Seeds Extracts of Ficus carica: In Vitro and In Silico Approaches.

Obesity and hyperlipidemia have become major disorders predominantly causing prevailing cardiovascular diseases and ultimately death. The prolonged use of anti-obesity drugs and statins for reducing obesity and blood lipid levels is leading toward adverse effects of kidneys and muscles, specifically rhabdomyolysis. The objective of this study is to evaluate potential of seeds of Ficus carica against hyperlipidemia. Various extracts and isolated compounds from fig seeds were analyzed and evaluated for their anti-hyperlipidemic potential. Methanol extract and its ethyl acetate fraction showed maximum pancreatic lipase inhibition of 61.93% and 86.45% in comparison to reference drug Orlistat. Four compounds isolated by HPLC-PDA technique were determined as Gallic acid, Catechin, Epicatechin, and Quercetin also showed strong potential to inhibit enzyme pancreatic lipase comparable to Orlistat. These isolated compounds were further analyzed for molecular docking and MM-GBSA studies. Three ligands, namely Quercetin, Epicatechin, and Catechin were found more effective against pancreatic lipase as these possessed docking scores (-9.881, -9.741, -9.410) higher to that of the reference ligand Orlistat (-5.273). The binding free energies of these compounds were -55.03, -56.54, and 60.35 kcal/mol, respectively. The results have shown that Quercetin has the highest binding affinity correlating with the highest inhibition of pancreatic lipase enzyme 1LPB. Hence, it is suggested that seeds of F. carica have promising anti-hyperlipidemic potential and foremost in reducing obesity.

Pharmacokinetic and molecular docking studies to pyrimidine drug using Mn3O4 nanoparticles to explore potential anti-Alzheimer activity.

Alzheimer disease (AD) is the cause of dementia and accounts for 60-80% cases. Tumor Necrosis Factor-alpha (TNF-α) is a multifunctional cytokine that provides resistance to infections, inflammation, and cancer. It developed as a prospective therapeutic target against multiple autoimmune and inflammatory disorders. Cholinergic insufficiency is linked to Alzheimer's disease, and several cholinesterase inhibitors have been created to treat it, including naturally produced inhibitors, synthetic analogs, and hybrids. In the current study, we tried to prepared compounds may also support the discovery and development of novel therapeutic and preventative drugs for Alzheimer's using manganese tetroxide nanoparticles (Mn3O4-NPs) as a catalyst to generate compounds with excellent reaction conditions. The Biginelli synthesis yields 4-(4-cyanophenyl)-6-oxo-2-thioxohexahydropyrimidine-5-carbonitrile when the 4-cyanobenzaldehyde, ethyl cyanoacetate, and thiourea were coupled with Mn3O4-NPs to produce compound 1. This multi-component method is non-toxic, safe, and environmentally friendly. The new approach reduced the amount of chemicals used and preserved time. Compound 1 underwent reactions with methyl iodide, acrylonitrile, chloroacetone, ethyl chloroacetate, and chloroacetic acid/benzaldehyde, each of the synthetized compounds was docked with TNF-α converting enzyme. These compounds may also support the discovery and development of novel therapeutic and preventative drugs for Alzheimer's disease. The majority of the produced compounds demonstrated pharmacokinetic features, making them potentially attractive therapeutic candidates for Alzheimer's disease treatment.

Molecular docking studies, DFT, and ADMET calculations of some flavonoids and their characteristic structural features involved in inhibition of pro-inflammatory enzymes.

Inflammation is an immune system response triggered by pathogens, damaged cells, or stimuli. Some regulatory enzymes, such as phosphodiesterase, hyaluronidase, collagenase, and lipoxygenase, play an essential role in the inflammatory process. Polyphenolic compounds, such as flavonoids, are active suppressors of inflammatory cytokines, modulators of transcription factors, and inflammation-related pathways. A set of flavonoid structures was screened and docked against inflammation pathway enzymes. Amentoflavone has been shown to cause interactions with phosphodiesterase enzymes, while Bilobetin and Silibinin demonstrated an increase in binding energy with collagenase enzymes. The retrieved compounds from the docking study were subjected to DFT theory. The results showed that the LUMO orbital is located on the flavonoid part. The thermochemical parameters indicated that Silibinin is more stable than other compounds. The ADMET profile predicted that Silibinin can be used orally among the compounds. Silibinin can be introduced as a promising anti-inflammatory agent demonstrating phosphodiesterase and collagenase inhibitory properties.

LC-ESI-MS/MS-based molecular networking, antioxidant, anti-glioma activity and molecular docking studies of Clematis graveolens.

Clematis graveolens Lindl., an indigenous climbing plant found in the Himalayan areas, is used by local communities for the treatment of neck tumors. The objective of this work is to examine the comprehensive metabolomic profile, antioxidant capability, in vitro and in silico anti-glioma effects on U-87 human glioma cell lines of the crude extract and fractions from C. graveolens. Liquid chromatography coupled with mass spectroscopy (LC-MS/MS) was used to establish detailed metabolite profiling of C. graveolens. The assessment of cell cytotoxicity was conducted using MTT cell viability assay on U-87 and BHK-21. Through molecular docking studies, the mode of inhibition and binding interaction between identified compounds and target proteins were also determined to evaluate the in vitro results. The use of LC-MS/MS-based global natural products social (GNPS) molecular networking analysis resulted in the identification of 27 compounds. The crude extract, ethyl acetate fraction, and chloroform fraction exhibited significant inhibitory activity against the U-87 cell lines, with IC50 values of 112.0, 138.1, and 142.7 µg/mL, respectively. The ethyl acetate fraction exhibited significant inhibitory concentration for 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) activity, 2,2-diphenyl-1-picrylhydrazyl (DPPH) activity and the metal chelation activity with IC50 value of 39.50 µg/mL, 32.27 µg/mL, and 53.46 µg/mL, respectively. The crude extract showed maximum total phenolic, and total flavonoid concentration measuring 338.7 µg GAE/mg, and 177.04 µg QE/mg, respectively. The findings of this study indicate that C. graveolens consists of a diverse range of active phytoconstituents that possess antioxidant and anti-glioma properties.

A Comprehensive Update of Anti-COVID-19 Activity of Heterocyclic Compounds.

The Coronavirus disease 2019 (COVID-19) pandemic is one of the most considerable health problems across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the major causative agent of COVID-19. The severe symptoms of this deadly disease include shortness of breath, fever, cough, loss of smell, and a broad spectrum of other health issues such as diarrhea, pneumonia, bronchitis, septic shock, and multiple organ failure. Currently, there are no medications available for coronavirus patients, except symptom-relieving drugs. Therefore, SARS-CoV-2 requires the development of effective drugs and specific treatments. Heterocycles are important constituents of more than 85% of the physiologically active pharmaceutical drugs on the market now. Several FDA-approved drugs have been reported including molnupiravir, remdesivir, ritonavir, oseltamivir, favipiravir, chloroquine, and hydroxychloroquine for the cure of COVID-19. In this study, we discuss potent anti-SARS-CoV-2 heterocyclic compounds that have been synthesized over the past few years. These compounds included; indole, piperidine, pyrazine, pyrimidine, pyrrole, piperazine, quinazoline, oxazole, quinoline, isoxazole, thiazole, quinoxaline, pyrazole, azafluorene, imidazole, thiadiazole, triazole, coumarin, chromene, and benzodioxole. Both in vitro and in silico studies were performed to determine the potential of these heterocyclic compounds in the fight against various SARS-CoV-2 proteins.

Facile one-pot synthesis and in silico study of new heterocyclic scaffolds with 4-pyridyl moiety: Mechanistic insights and X-ray crystallographic elucidation.

4-Acetylpyridine 1 and malononitrile 2 were allowed to react in a 3MCRs with dimedone 3a or cyclohexa-1,3-dione 3b under reflux to afford 4-methyl-4-(pyridin-4-yl)-5,6,7,8-tetrahydro-4H-chromene derivatives 4a,b respectively. The mechanism of the reaction has been studied and the structures elucidated by analytical, spectral as well as X-ray crystallographic data. Heterocyclic compounds find widespread application in pharmaceutical and agrochemical products. Docking analyses were performed on the synthesized compounds to assess their binding modes with various amino acids of the target protein tubulin (PDB Code - 1SA0). The results indicated promising binding scores for compounds 4a and 4b, suggesting a strong affinity for the tubulin binding site. Finally, ADMET for the synthesized compounds 4a, 4b, 5, 8a and 8b were carried out. The drug likeness and pharmacokinetic properties of the prepared compounds were also evaluated. Notably, all of the novel compounds adhered to Lipinski's rule (Ro5) without any violations.

Chitosan-sulfonic acid-catalyzed green synthesis of naphthalene-based azines as potential anticancer agents.

Aim: This study focuses on advancing green chemistry in anticancer drug discovery, particularly through the synthesis of azine derivatives with a naphthalene core using CS-SO3H as a catalyst. Methods: Novel benzaldazine and ketazine derivatives were synthesized using (E)-(naphthalen-1-ylmethylene)hydrazine and various carbonyl compounds. The methods employed included thermal and grinding techniques, utilizing CS-SO3H as an eco-friendly and cost-effective catalyst. Results: The approach resulted in high yields, short reaction times and demonstrated catalyst reusability. Cytotoxicity tests highlighted compounds 3b, 11 and 13 as potent against the HEPG2-1. Conclusion: This study successfully aligns with the objectives of eco-conscious drug development in organic chemistry. Molecular docking and in silico studies further indicate the potential of these ligands as antitumor medicines, with favorable oral bioavailability properties.

Design, synthesis, and biological evaluation of piperazine derivatives involved in the 5-HT1AR/BDNF/PKA pathway.

In this study, four series of piperazine derivatives were designed, synthesised and subjected to biological test, and compound 6a with potential antidepressant activity was obtained. An affinity assay of compound 6a with 5-hydroxytryptamine (serotonin, 5-HT)1A receptor (5-HT1AR) was undertaken, and the effects on the 5-HT level in the brains of mice were also tested. The results showed that compound 6a had the best affinity with 5-HT1AR (Ki = 1.28 nM) and significantly increased the 5-HT level. The expression levels of 5-HT1AR, BDNF, and PKA in the hippocampus were analysed by western blot and immunohistochemistry analyses. The results showed that the expression of 5-HT1AR, BDNF, and PKA in the model group was reduced compared to that of the control group, and compound 6a could reverse this phenomenon. Molecular docking was performed to investigate the interactions of the studied compound 6a with 5-HT1AR on the molecular level.

In silico discovery of novel calcineurin inhibitors using ligand-based 3-D pharmacophore modelling and molecular dynamics simulation.

Calcineurin is a serine-threonine protein phosphatase that is activated with the binding of calmodulin in the presence of increased calcium concentration and has a major role in various signaling pathways. Its role in regulating homeostasis, developmental processes, and different disease progression has already been reported. The dysregulated Ca2+/calcineurin/NFAT1-4 pathway is observed in Autoimmune disorders and hence the use of Calcineurin inhibitors like Cyclosporin A (CsA) and Tacrolimus (FK506) is widely done in such cases. Recent studies indicate the uncontrolled overexpression of the Calcineurin protein in the pathophysiological pathway of neurodegenerative diseases. The in vitro and animal model studies with standard calcineurin inhibitors (CnIs), which are widely labeled as immunosuppressant drugs, have shown a significant reduction of neurodegeneration in respective models. These results compel the identification of novel calcineurin inhibitors against neurodegenerative diseases. With this scenario, the present work focuses on the computer-aided identification of novel CnIs via ligand-based 3-D pharmacophore modelling. Known CnIs, CsA, and FK506, were used to build the pharmacophore models which were validated and screened against external databases to retrieve possible hits. Docking investigations, pharmacokinetic properties, and molecular dynamics simulations along with toxicity predictions were performed on the hits that were obtained. According to the study, a total of 5 molecules ILB 162, ILB 005, ILB 439, ILB 390, and ILB 198, were found to be the best calcineurin inhibitors with binding affinity in the range of -9.7 to -9.0 Kcal/mol with 1MF8 (PDB). The stability of interactions of these molecules was further validated via Molecular dynamics simulation studies to confirm these to be the potential calcineurin-inhibiting molecules. HIGHLIGHTSCalcineurin inhibitors can be a novel therapeutic candidate against neurodegenerative diseases.The identification of novel Calcineurin inhibitors was done in silico using ligand-based 3-D pharmacophore modelling using Ligand Scout Essential 4.4. software.The model could identify 440 hits from various external databases like PubChem (2432 molecules), ChemSpider, MayBridge, DrugBank, and e-Drug 3D by Cheminformatic Tools and Databases for Pharmacology.Out of which 5 molecules: ILB 162, ILB 005, ILB 439, ILB 390, and ILB 198, were found to be the best calcineurin inhibitors with binding affinity in the range of -9.7 to -9.0 Kcal/mol with 1MF8 (PDB) which were further confirmed to be the best CnI candidates via Molecular dynamics simulation studies.Communicated by Ramaswamy H. Sarma.

In silico prediction of mutation sites for anthranilate synthase from Serratia marcesens to deregulate tryptophan feedback inhibition.

Allosteric feedback inhibition of the committed step in amino acid biosynthetic pathways is a major concern for production of amino acids at industrial scale. Anthranilate synthase (AS) catalyzes the first reaction of tryptophan biosynthetic pathway found in microorganisms and is feedback inhibited by its own product i.e. tryptophan. Here, we identified new mutant sites in AS using computational mutagenesis approach. MD simulations (20 ns) followed by MMPBSA and per residue decomposition energy analysis identified seven amino acid residues with best binding affinity for tryptophan. All 19 mutant structures were generated for each identified amino acid residue followed by simulation to evaluate effect of mutation on protein stability. Later, molecular docking studies were employed to generate mutant-tryptophan complex and structures with binding energies (kcal/mol) much higher than wild-type AS were selected. Finally, two mutants i.e., S37W and S37H were identified on the basis of positive binding scores and loss of tryptophan binding inside pocket. Further, MD simulations run for 200 ns were performed over these mutant-tryptophan complexes followed by RMSD, RMSF, radius of gyration , solvent accessible surface area , intra-protein hydrogen bond numbers, principal component analysis, free energy landscape (FEL) and secondary structure analysis to rationale effect of mutations on stability of protein. Cross correlation analysis of mutant site amino acids (S37W) with key residues of catalytic site (G325, T326, H395 and G482) was done to evaluate the effect of mutations on catalytic site conformation. Current computational mutagenesis approach predicted two mutants S37W and S37H with proposed deregulated feedback inhibition by tryptophan and retained catalytic activity.Communicated by Ramaswamy H. Sarma.

Synthesis and In Silico Studies of Quinazolinones as PARP-1 Inhibitors.

BACKGROUND: Cancer is a leading threat to humankind, accounting for nearly one million deaths in 2018, and the expected number of cancer-related deaths in 2040 is more than 16 million. The most common causes of cancer deaths are lung, colorectal, stomach, liver and breast cancer, while the highest number of new cancer cases belong to lung, breast, colorectal, prostate, stomach and liver cancer. INTRODUCTION: PARP-1 is an enzyme that plays an important role in DNA repair, cell propagation/survival and death due to its influence on numerous biological processes. Quinazolinones represent an important scaffold in medicinal chemistry and have a broad spectrum of biological activities. METHOD: In this study, we have synthesized quinazolinones by reaction of 2-aminobenzamide and substituted aldehydes. Molecular docking studies of synthesized compounds were performed for their PARP-1 binding affinities using Schrodinger 2016 software. In silico ADME studies were also performed for the synthesized compounds using the QikProp tool of Schrodinger software. RESULTS: Results of molecular docking studies indicated that synthesized quinazolinones had a good affinity towards active site of PARP-1 and compound 4 had the best docking score (-10.343). Results of ADME studies indicated the drug-like properties of synthesized compounds, which make them suitable drug candidates. CONCLUSION: All the synthesized compounds have a better docking score than niraparib (-9.05). Further, the synthesized compounds have a favorable ADME profile. Therefore, they may serve as important leads in discovering PARP-1 inhibitors.

Identification of coastal pesticide pollutants as potent inhibitors of Bacillus pasteurii urease mediated calcium carbonate precipitation: a computational approach.

Microbially induced calcite precipitation (MICP) through urease enzyme has attained a lot of recognition in various fields of civil engineering and geotechnology for stabilizing the strength of soil and various concrete materials. The activity of urease has been found to be affected by various factors like temperature, substrate concentrations, pH of the medium, presence of inhibitors, etc. Through this study, the outcome of the interaction of pesticides (commonly found in Indian coastal regions) on Bacillus pasteurii urease, a major organism reported for MICP studies has been investigated in silico. The results from the study revealed that the enzyme has higher interactions of -4.1, -3.2, and -3.4 kJ/mol with common pesticides like dichloro diphenyl dichloro ethane(DDD), dichloro diphenyl trichloroe thane (DDT), and methyl parathion of organochlorides and organophosphates class. From the molecular dynamics simulation analysis, complex 1 (DDD -receptor) has been found to have the highest and more compact structure followed by methyl parathion -receptor. Prime MM-GBSA analysis also revealed the highest binding energy of -27.8 kcal/mol with the protein and DDD. Thus, it can be inferred from the current study that pesticides, particularly, DDD, DDT, and methyl parathion present in the coastal areas may have an impact on urease. This interaction can result in the inhibition of the urease activity of B. pasteurii, thus preventing the biomineralization process. This study would be the first report on the computational approach to understanding the interaction of prominent pesticides on the coastal region and B. pasteurii urease.Communicated by Ramaswamy H. Sarma.

Synthesis, Anticancer Evaluation and in Silico Studies of 1,4-Dihydropyridines.

An efficient 1,4-dihydropyridine synthesis under mild conditions has been developed. Numerous substrates were tested, with yields of 1,4-dihydropridines ranging from good to excellent and a wide range of functional group tolerance. A549, HT-29, and HepG2 cancer cells were used to investigate the anticancer efficacy of each of the produced compounds. Additionally, in-silico docking studies were conducted to understand the structure-based features of the anticancer mechanism with the cancer medication target of Adenosine A2A receptor as well as the molecular level interactions of the compounds.

Antiarthritic potential of the butanol fraction of Sesuvium sesuvioides: An in vitro, in vivo, and in silico evaluation.

Sesuvium sesuvioides (Fenzl) Verdc (Aizoaceae) has been traditionally used in the treatment of inflammation, arthritis, and gout. However, its antiarthritic potential has not been evaluated scientifically. The current study was designed to assess the antiarthritic properties of the n-butanol fraction of S. sesuvioides (SsBu) by phytochemical analysis, in vitro and in vivo pharmacological activities, and in silico studies. Phytochemical analysis showed total phenolic contents (90.7 ± 3.02 mg GAE/g) and total flavonoid contents (23.7 ± 0.69 mg RE/g), and further analysis by GC-MS identified possible bioactive phytocompounds belonging to phenols, flavonoids, steroids, and fatty acids. The in vitro antioxidant potential of SsBu was assessed by DPPH (175.5 ± 7.35 mg TE/g), ABTS (391.6 ± 17.1 mg TE/g), FRAP (418.2 ± 10.8 mg TE/g), CUPRAC (884.8 ± 7.97 mg TE/g), phosphomolybdenum (5.7 ± 0.33 mmol TE/g), and metal chelating activity (9.04 ± 0.58 mg EDTAE/g). Moreover, in the in vitro studies, inhibition (%) of egg albumin and bovine serum albumin denaturation assays showed that the anti-inflammatory effect of SsBu at the dose of 800 µg/ml was comparable to that of diclofenac sodium used as a standard drug. The in vivo antiarthritic activity was assessed to determine the curative impact of SsBu against formalin-induced (dose-dependent significant (p < 0.05) effect 72.2% inhibition at 750 mg/kg compared to standard; 69.1% inhibition) and complete Freund's adjuvant-induced arthritis (40.8%; inhibition compared to standard, 42.3%). SsBu significantly controlled PGE-2 level compared to the control group (p < 0.001) and restored the hematological parameters in rheumatoid arthritis. Treatment with SsBu significantly reduced oxidative stress by reinstating superoxide dismutase, GSH, and malondialdehyde along with pro-inflammatory markers (IL-6 and TNF-α) in arthritic rats. Molecular docking revealed the antiarthritic role of major identified compounds. Kaempferol-3-rutinoside was found to be more potent for COX-1 (-9.2 kcal/mol) and COX-2 inhibition (-9.9 kcal/mol) than diclofenac sodium (COX-1, -8.0 and COX-2, -6.5 kcal/mol). Out of the 12 docked compounds, two for COX-1 and seven for COX-2 inhibition showed more potent binding than the standard drug. The results from the in vitro, in vivo, and in silico approaches finally concluded that the n-butanol fraction of S. sesuvioides had antioxidant and antiarthritic potential, which may be due to the presence of potential bioactive compounds.

Synthesis, antidiabetic activity and molecular docking studies of novel aryl benzylidenethiazolidine-2,4-dione based 1,2,3-triazoles.

A series of novel aryl benzylidenethiazolidine-2,4-dione based 1,2,3-triazoles synthesized in a straightforward route consisting of benzylidenethiazolidine-2,4-dione and 1,2,3-triazole pharmacophores. The new scaffolds tested for in vitro antidiabetic activity by inhibition of aldose reductase enzyme and its inhibition measured in half of Inhibition Concentration (IC50). The activity results correlated with standard reference Sorbinil (IC50: 3.45 ± 0.25 µM). Among all the titled compounds 8f (1.42 ± 0.21 µM), 8d (1.85 ± 0.39 µM), 13a (1.94 ± 0.27 µM) and 8b (1.98 ± 0.58 µM) shown potent activity. In addition, molecular docking results against the crystal structure of aldose reductase (PDB ID: 1PWM) revealed that the binding affinities shown by all synthesized compounds are higher than the reference compound Sorbinil. The docking scores, H-bond interactions, and hydrophobic interactions well defined inhibition strength of all compounds.

Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies.

Leishmaniasis is a neglected tropical disease, and there is an emerging need for the development of effective drugs to treat it. To identify novel compounds with antileishmanial properties, a novel series of functionalized spiro[indoline-3,2'-pyrrolidin]-2-one/spiro[indoline-3,3'-pyrrolizin]-2-one 23a-f, 24a-f, and 25a-g were prepared from natural-product-inspired pharmaceutically privileged bioactive sub-structures, i.e., isatins 20a-h, various substituted chalcones 21a-f, and 22a-c amino acids, via 1,3-dipolar cycloaddition reactions in MeOH at 80 °C using a microwave-assisted approach. Compared to traditional methods, microwave-assisted synthesis produces higher yields and better quality, and it takes less time. We report here the in vitro antileishmanial activity against Leishmania donovani and SAR studies. The analogues 24a, 24e, 24f, and 25d were found to be the most active compounds of the series and showed IC50 values of 2.43 µM, 0.96 µM, 1.62 µM, and 3.55 µM, respectively, compared to the standard reference drug Amphotericin B (IC50 = 0.060 µM). All compounds were assessed for Leishmania DNA topoisomerase type IB inhibition activity using the standard drug Camptothecin, and 24a, 24e, 24f, and 25d showed potential results. In order to further validate the experimental results and gain a deeper understanding of the binding manner of such compounds, molecular docking studies were also performed. The stereochemistry of the novel functionalized spirooxindole derivatives was confirmed by single-crystal X-ray crystallography studies.

Design and synthesis of neoteric benzylidene amino-benzimidazole scaffolds for antioxidant and anti-inflammatory activity.

Aim: To design a series of neoteric benzylidene amino-benzimidazole derivatives and to synthesize and evaluate them for anti-inflammatory and antioxidant potential. Methods: The designed target scaffolds were synthesized and appraised for in vitro antioxidant action and in vivo anti-inflammatory potential. AutoDock Vina software was employed for design; the Mannich reaction was used for synthesis; and antioxidant and anti-inflammatory potential were demonstrated by the 2,2-diphenyl-1-picryl hydrazyl free-radical scavenging assay and carrageenan-induced paw edema method, respectively. Results: Methyl-incorporating molecules 3-(2-((2-methylbenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one (6c) and 3-(2-((4-methylbenzylidene)amino-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one (6j) showed remarkable antioxidant and anti-inflammatory action, followed by compounds 6f, 6e and 6i containing 3-CH3, 2-OH, 4-F substituents, respectively. Conclusion: The designed analogs were dynamically confined within the active site of cyclooxygenase-2, and in vitro and in vivo results agreed with molecular docking studies.

Anti-inflammatory potential of 1-O-methyl chrysophanol from Amycolatopsis thermoflava ICTA 103: an exploratory study.

The present study was designed to investigate the anti-inflammatory potential of Amycolatopsis thermoflava producing 1-O-methyl chrysophanol (OMC), a member of the hydroxyanthraquinone family. The anti-inflammatory potential was evaluated initially through in silico analysis against tumor necrosis factor- α and cyclooxygenase-2. The same activity was further confirmed based on the in vitro protein denaturation method as well as in vivo by a carrageenan-induced paw edema model in rats. The OMC compound was isolated, purified, and characterized from the fermentation broth of Amycoloptosis thermoflava. In vitro data revealed that the OMC possesses significant protein denaturation properties with an IC50 of 63.50±2.19 µg/ml higher than the standard drug, with an IC50 value of 71.42±0.715 µg/ml. The percentage of inhibition in paw swelling was observed to be 40.03±5.5 in OMC-treated group, which is comparable to the standard group (52.8±4.7). The histopathological evaluation and immunohistochemistry revealed the anti-inflammatory potential of OMC.

Design, Synthesis, Molecular Docking, and Molecular Dynamics Simulation Studies of Novel 3-Hydroxypyridine-4-one Derivatives as Potential Acetylcholinesterase Inhibitors.

Researchers have focused on inhibiting acetylcholinesterase for Alzheimer's disease treatment. In this study, some novel AChE inhibitors were synthesized using hydroxypyridin-4-one plus benzylpiperidine scaffolds which were evaluated using Ellman's method. Accordingly, ((1-(4-methoxyphenethyl)piperidin-4-yl)amino)methyl)-5-hydroxy-1-methylpyridin-4(1H)-one (VIId ) showed weaker but promising AChE inhibition compared to donepezil (IC50 =143.090 nM). The average RMSD values of VIId was found to be 2.25 indicated less structural changes in the active site residues. The phenyl group of the phenyl-ethyl-N-piperidine moiety of VIId formed hydrophobic interactions with Trp285 and Tyr340. There was a π-cation interaction between nitrogen atom of piperidine ring and Phe294. Another π-cation interaction was found between type 2 amine of linker and Trp85. Piperidine ring interacted with Tyr336, Tyr123, and Phe337 through hydrophobic interactions. Indeed, the VIId was predicted to be absorbed across the gastrointestinal tract, though it may be pumped out by P-gp. Indeed, VIId can permeate through the blood brain barrier. MD simulation studies revealed that benzyloxy moiety plays a role similar to benzylpiperidine moiety of donepezil in binding to the active site residues. Also, carbonyl group functioned similar to indanone ketone group. Overall; further research on VIId may lead to introduction of a novel class of AChE inhibitors.

Structural and functional insights into a novel homozygous missense pathogenic variant in CUL7 identified in consanguineous Pakistani family.

3M syndrome is a rare genetic familial disorder characterized by short stature, growth retardation, facial dysmorphism, skeletal abnormalities, fleshy protruding heels, and normal intelligence, caused by mutations in the CUL7, OBSL1 and CCDC8 genes. In the present study, a novel homozygous missense variant of CUL7 (NP_001161842.1, c.4493T > C, p.L1498P) has been identified in a consanguineous Pakistani family by whole exome sequencing. In silico structural evaluation, molecular docking and simulation studies of mutant CUL7 provides substantial evidence about its crucial role in the progression of discussed ailment. The newly discovered variant significantly altered the protein's three dimensional structure, leading to abnormal interaction with binding proteins. This computational and experimental investigation provides useful information to drug developers for the synthesis of novel therapeutics against the discussed ailment.Communicated by Ramaswamy H. Sarma.