A systematic review on understanding the mechanistic pathways and clinical aspects of natural CDK inhibitors on cancer progression.: Unlocking cellular and biochemical mechanisms.

Cell division, differentiation, and controlled cell death are all regulated by phosphorylation, a key biological function. This mechanism is controlled by a variety of enzymes, with cyclin-dependent kinases (CDKs) being particularly important in phosphorylating proteins at serine and threonine sites. CDKs, which contain 20 unique components, serve an important role in regulating vital physiological functions such as cell cycle progression and gene transcription. Methodologically, an extensive literature search was performed using reputable databases such as PubMed, Google Scholar, Scopus, and Web of Science. Keywords encompassed "cyclin kinase," "cyclin dependent kinase inhibitors," "CDK inhibitors," "natural products," and "cancer therapy." The inclusion criteria, focused on relevance, publication date, and language, ensured a thorough representation of the most recent research in the field, encompassing articles published from January 2015 to September 2023. Categorization of CDKs into those regulating transcription and those orchestrating cell cycle phases provides a comprehensive understanding of their diverse functions. Ongoing clinical trials featuring CDK inhibitors, notably CDK7 and CDK4/6 inhibitors, illuminate their promising potential in various cancer treatments. This review undertakes a thorough investigation of CDK inhibitors derived from natural (marine, terrestrial, and peptide) sources. The aim of this study is to provide a comprehensive comprehension of the chemical classifications, origins, target CDKs, associated cancer types, and therapeutic applications.

Molecular modeling of novel 2-aminopyridine derivatives as potential JAK2 inhibitors: a rational strategy for promising anticancer agents.

Janus kinase 2(JAK2) is a potential target for anticancer drugs in the treatment of numerous myeloproliferative diseases due to its central role in the JAK/STAT signaling cascade. In this study, the binding behavior of 2 amino-pyridine derivatives as JAK2 inhibitors was investigated by using multifaceted strategies including 3D-QSAR, molecular docking, Fingerprint analysis, MD simulations, and MM-PBSA calculations. A credible COMFA (q2 = 0.606 and r2 = 0.919) and COMSIA (q2 = 0.641 and r2 = 0.992) model was developed, where the internal and external validation revealed that the obtained 3D-QSAR models could be capable of predicting bioactivities of JAK2 inhibitors. The structural criteria provided by the contour maps of model were used to computationally develop more potent 100 new JAK2 inhibitors. Docking studies were conducted on the model data set and newly developed compounds (in-house library) to demonstrate their binding mechanism and highlight the key interacting residues within JAK2 active site. The selected docked complexes underwent MD simulation (100 ns), which contributed in the further study of the binding interactions. Binding free energy analyses (MMGB/PBSA) revealed that key residues such as Glu930, Leu932 (hinge region), Asp939 (solvent accessible region), Arg980, Asn981and Asp994 (catalytic site) have a significantly facilitate ligand-protein interactions through H-bonding and van der Waals interactions. The preliminary in-silico ADMET evaluation revealed encouraging results for all the modeled and in-house library compounds. The findings of this research have the potential to offer valuable recommendations for the advancement of novel, potent, and efficacious JAK2 inhibitors. Overall, this work has successfully employed a wide range of computer-based methodologies to understand the interaction dynamics between 2-amino-pyridine derivatives and the JAK2 enzyme, which is a crucial target in myeloproliferative disorders.Communicated by Ramaswamy H. Sarma.

Biochemical, Toxicological, and in Silico Aspects of Trillium govanianum Wall. ex D.Don (Trilliaceae): A Rich Source of Natural Bioactive Compounds.

Trillium govanianum is a high-value medicinal herb, having multifunctional traditional and culinary uses. The present investigation was carried out to evaluate the phytochemical, biological and toxicological parameters of the T. govanianum Wall. ex D. Don (Family: Trilliaceae) roots collected from Azad Kashmir, Pakistan. Phytochemical profiling was achieved by determining total bioactive contents (total phenolic and flavonoid contents) and UHPLC-MS analysis. For biological evaluation, antioxidant activities (DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum, and metal chelation assays) and enzyme inhibition activities (against AChE, BChE, glucosidase, amylase, and tyrosinase) were performed. Moreover, cytotoxicity was assessed against three human carcinoma cell lines (MDA-MB-231, CaSki, and DU-145). The tested extract was found to contain higher total phenolics (7.56 mg GAE/g dry extract) as compared to flavonoid contents (0.45 mg RE/g dry extract). Likewise, for the antioxidant activity, higher CUPRAC activity was noted with 39.84 mg TE/g dry extract values. In the case of enzyme assays, higher activity was pointed out against the cholinesterase, glucosidase and tyrosinase enzymes. The plant extract displayed significant cytotoxicity against the cell lines examined. Moreover, the in-silico studies highlighted the interaction between the important phytochemicals and tested enzymes. To conclude, the assessed biological activity and the existence of bioactive phytochemicals in the studied plant extract may pave the way for the development of novel pharmaceuticals.

Integrated computational approaches for designing potent pyrimidine-based CDK9 inhibitors: 3D-QSAR, docking, and molecular dynamics simulations.

CDK9 is an emerging target for the development of anticancer drugs. The development of CDK9 inhibitors with significant potency had consistently posed a formidable challenge. In the current research, a number of computational methodologies, such as, 3D-QSAR, molecular docking, fingerprint analysis, molecular dynamic (MD) simulations followed by MMGB/PBSA and ADMET studies were used systemically to uncover the binding mechanism of pyrimidine derivatives against CDK9. The CoMFA and CoMSIA models having high q2 (0.53, 0.54) and r2 values (0.96, 0.93) respectively indicating that model could accurately predict the bioactivities of CDK9 inhibitors. Using the R-group exploration technique implemented by the Spark™ by Cresset group, the structural requirements revealed by the contour maps of model were utilized strategically to create an in-house library of 100 new CDK9 inhibitors. Additionally, the compounds from the in-house library were mapped into 3D-QSAR model which predicted pIC50 values comparable to the experimental values. A comparison between 3D-QSAR generated contours and molecular docking conformation of ligands was performed to elucidate the essentials of CDK9 inhibitor design. MD simulations (100 ns) were performed on the selected docked complexes A21, A14 and D98 which contributed in validating the binding interactions. According to the findings of binding free energy analysis (MMGB/PBSA), It was observed that residues CYS106 and GLU107 had a considerable tendency to facilitate ligand-protein interactions via H-bond interactions. The aforementioned findings have the potential to enhance researchers comprehension of the mechanism underlying CDK9 inhibition and may be utilized in the development of innovative and efficacious CDK9 inhibitors.

Synthesis of novel nonsteroidal anti-inflammatory galloyl ß-sitosterol-loaded lignin-capped Ag-based drug.

Biocompatible anti-inflammatory lignin-capped Ag (LCAg) nanoparticles (NPs) were synthesized for the delivery of galloyl ß-sitosterol (Galloyl-BS). ß-Sitosterol (BS) is effective against inflammatory responses, like cancer-induced inflammations. BS was modified via gallic acid esterification to enhance its anti-inflammatory potential. LCAg NPs were synthesized by a green method and loaded with galloyl-BS. For comparison, pure BS was also loaded onto LCAg NPs in a separate assembly. The antioxidant potential of Galloyl-BS was greater (IC50 177 µM) than pure BS. Materials were characterized by FT-IR, SEM, XRD, and Zeta potential. Using UV-Vis spectroscopy, drug release experiments were performed by varying pH, time, concentration, and temperature. Maximum drug release was observed after 18 h at pH 6 and 40 °C. Galloyl-BS showed improved drug loading efficiency, release %age, and antioxidant activity compared to pure BS when loaded onto LCAg NPs. DLCAg exhibited excellent anti-inflammatory activity in rat models. These findings indicate that galloyl-BS (drug)-loaded LCAg (DLCAg) NPs have the potential as an anti-inflammatory agent without any prior release and scavenging in normal cells.

Preparation of Tamsulosin Hydrochloride-Loaded Mucoadhesive In Situ Gelling Polymeric Formulation for Nasal Delivery in Geriatrics.

This study aimed to prepare tamsulosin hydrochloride (HCl)-loaded in situ gelling formulation by using hydroxypropyl methylcellulose (HPMC), gellan gum, poloxamer 188, and benzalkonium chloride. Physicochemical evaluation of formulations included determination of pH, viscosity, gelation time, gel strength, drug content, and sterility. In silico study was performed to analyze interactions between polymers, drug, and mucin glycoprotein. In vitro degradation time, drug release, ex vivo mucoadhesion time, permeation, in vivo pharmacokinetics, and stability studies were performed to assess the formulation. Formulations were transparent and displayed acceptable physicochemical attributes. Tamsulosin HCl and polymers interacted via non-covalent interactions. HPMC formed hydrogen bonds, hydrophobic and van der Waals interactions with mucin protein while the drug formed hydrogen bonds only. Gel formulation degraded in simulated nasal fluid within 24 h. In situ gelling formulation showed 83.8 ± 1.7% drug release and remained adhered to the mucosa for 24.5 ± 1 h. A higher (~ 1.85 times) drug permeation was recorded through mucosa within 6 h by in situ gelling formulation when compared to control counterparts (aqueous solution of drug and in situ gelling formulation without poloxamer 188). Nasal administration of tamsulosin HCl by using in situ gelling formulation led to a ~ 3.3 and ~ 3.5 times, respectively, higher Cmax (maximum plasma concentration) and AUCtotal (total area under the curve) than the orally administered aqueous solution. Relative bioavailability of drug delivered by nasal in situ gelling formulation was 3.5 times the oral counterpart. These results indicated that the prepared in situ gelling formulation can act as a promising candidate for systemic administration of tamsulosin HCl.

3D-QSAR, docking and molecular dynamics simulations of novel Pyrazolo-pyridazinone derivatives as covalent inhibitors of FGFR1: a scientific approach for possible anticancer agents.

Developing highly potent covalent inhibitors of Fibroblast growth factor receptors 1 (FGFR1) has always been a challenging task. In the current study, various computational techniques, such as 3D-QSAR, covalent docking, fingerprinting analysis, MD simulation followed by MMGB/PBSA, and per-residue energy decomposition analysis were used to explore the binding mechanism of pyrazolo[3,4-d]pyridazinone derivatives to FGFR1. The high q2 and r2 values for the CoMFA and CoMSIA models, suggest that the constructed 3D-QSAR models could reliably predict the bioactivities of FGFR1 inhibitors. The structural requirements revealed by the model's contour maps were strategically used to computationally create an in-house library of more than 100 new FGFR1 inhibitors using the R-group exploration technique implemented in the SparkTM software. The compounds from the in-house library were also mapped in the 3D-QSAR model that predicts comparable pIC50 values with the experimental values. A comparison between 3D-QSAR generated contours and molecular docking conformation of ligands was performed to reveal the fundamentals to design potent FGFR1 covalent inhibitors. The estimated binding free energies (MMGB/PBSA) for the selected compounds were in agreement with the experimental value ranking of their binding affinities towards FGFR1. Furthermore, per-residue energy decomposition analysis has identified Arg627 and Glu531 to contribute significantly in improved binding affinity of compound W16. During ADME analysis, the majority of in-house library compounds exhibited pharmacokinetic properties superior to those of experimentally produced compounds. These new compounds may help researchers better understand FGFR1 inhibition and lead to the creation of novel, potent FGFR1 inhibitors.Communicated by Ramaswamy H. Sarma.

Molecular modeling of pyrrolo-pyrimidine based analogs as potential FGFR1 inhibitors: a scientific approach for therapeutic drugs.

Fibroblast growth factor receptors 1 (FGFR1) is an emerging target for the development of anticancer drugs. Uncontrolled expression of FGFR1 is strongly associated with a number of different types of cancers. Apart from a few FGFR inhibitors, the FGFR family members have not been thoroughly studied to produce clinically effective anticancer drugs. The application of proper computational techniques may aid in understanding the mechanism of protein-ligand complex formation, which may provide a better notion for developing potent FGFR1 inhibitors. In this study, a variety of computational techniques, including 3D-QSAR, flexible docking and MD simulation followed by MMGB/PBSA, H-bonds and distance analysis, have been performed to systematically explore the binding mechanism of pyrrolo-pyrimidine derivatives against FGFR1. The 3D-QSAR model was generated to deduce the structural determinants of FGFR1 inhibition. The high q2 and r2 values for the CoMFA and CoMSIA models indicated that the created 3D-QSAR models could reliably predict the bioactivities of FGFR1 inhibitors. The computed binding free energies (MMGB/PBSA) for the selected compounds were consistent with the ranking of their experimental binding affinities against FGFR1. Furthermore, per-residue energy decomposition analysis revealed that the residues Lys514 in catalytic region, Asn568, Glu571 in solvent accessible portion and Asp641 in DFG motif exhibited a strong tendency to mediate ligand-protein interactions through the hydrogen bonding and Van Der Waals interactions. These findings may benefit researchers in gaining better knowledge of FGFR1 inhibition and may serve as a guideline for the development of novel and highly effective FGFR1 inhibitors.Communicated by Ramaswamy H. Sarma.

Fabrication and employment of cobalt-doped yttrium iron garnets for the electrochemical analysis of anti-diabetic, metformin in serum of type 2 diabetes mellitus patients.

Metformin (MET) is an anti-diabetic drug employed as the first-line therapy for patients of type II diabetes mellitus (T2DM). Overdosage of drugs leads to severe outcomes, and its monitoring in biofluids is vital. The present study develops cobalt-doped yttrium iron garnets and employs them as an electroactive material immobilized on a glassy carbon electrode (GCE) for the sensitive and selective detection of metformin via electroanalytical techniques. The fabrication procedure via the sol-gel method is facile and gives a good yield of nanoparticles. They are characterized by FTIR, UV, SEM, EDX, and XRD. Pristine yttrium iron garnet particles are also synthesized for comparison, where the electrochemical behaviors of varying electrodes are analyzed via cyclic voltammetry (CV). The activity of metformin at varying concentrations and pH is investigated via differential pulse voltammetry (DPV), and the sensor generates excellent results for metformin detection. Under optimum conditions and at a working potential of 0.85 V (vs. Ag/AgCl/3.0 M KCl), the linear range and limit of detection (LOD) obtained through the calibration curve are estimated as 0-60 µM and 0.04 µM, respectively. The fabricated sensor is selective for metformin and depicts a blind response toward interfering species. The optimized system is applied to directly measure MET in buffers and serum samples of T2DM patients.

Deep learning in drug discovery: a futuristic modality to materialize the large datasets for cheminformatics.

Artificial intelligence (AI) development imitates the workings of the human brain to comprehend modern problems. The traditional approaches such as high throughput screening (HTS) and combinatorial chemistry are lengthy and expensive to the pharmaceutical industry as they can only handle a smaller dataset. Deep learning (DL) is a sophisticated AI method that uses a thorough comprehension of particular systems. The pharmaceutical industry is now adopting DL techniques to enhance the research and development process. Multi-oriented algorithms play a crucial role in the processing of QSAR analysis, de novo drug design, ADME evaluation, physicochemical analysis, preclinical development, followed by clinical trial data precision. In this study, we investigated the performance of several algorithms, including deep neural networks (DNN), convolutional neural networks (CNN) and multi-task learning (MTL), with the aim of generating high-quality, interpretable big and diverse databases for drug design and development. Studies have demonstrated that CNN, recurrent neural network and deep belief network are compatible, accurate and effective for the molecular description of pharmacodynamic properties. In Covid-19, existing pharmacological compounds has also been repurposed using DL models. In the absence of the Covid-19 vaccine, remdesivir and oseltamivir have been widely employed to treat severe SARS-CoV-2 infections. In conclusion, the results indicate the potential benefits of employing the DL strategies in the drug discovery process.Communicated by Ramaswamy H. Sarma.

Correction to Therapeutic Potential of Standardized Extract of Melilotus indicus (L.) All. and Its Phytochemicals against Skin Cancer in Animal Model: In Vitro, In Vivo, and In Silico Studies.

[This corrects the article DOI: 10.1021/acsomega.2c03053.].

Therapeutic Potential of Standardized Extract of Melilotus indicus (L.) All. and Its Phytochemicals against Skin Cancer in Animal Model: In Vitro, In Vivo, and In Silico Studies.

Melilotus indicus (L.) All. is known to have anti-inflammatory and anticancer properties. The present study explored the in vivo skin carcinogenesis attenuating potential of ethanolic extract of M. indicus (L.) All. (Miet) in a 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin cancer model. The ethanolic extract of the plant was prepared by a maceration method. HPLC analysis indicated the presence of quercetin in abundance and also various other phytoconstituents. DPPH radical scavenging assay results showed moderate antioxidant potential (IC50 = 93.55 ± 5.59 µg/mL). A topical acute skin irritation study showed the nonirritant nature of Miet. Data for the skin carcinogenic model showed marked improvement in skin architecture in Miet and its primary phytochemicals (quercetin and coumarin) treated groups. Miet 50% showed comparable effects with 5-fluorouracil. Significant (p < 0.05) anticancerous effects were seen in coumarin-quercetin combination-treated animals than in single agent (coumarin and quercetin alone)-treated animals. Chorioallantoic membrane (CAM) assay results showed the antiangiogenic potential of Miet. Treatment with Miet significantly down-regulated the serum levels of CEA (carcinoembryonic antigen) and TNF-α (Tumor necrosis factor-α). Data for the docking study indicated the binding potential of quercetin and coumarin with TNF-α, EGFR, VEGF, and BCL2 proteins. Thus, it is concluded that Miet has skin cancer attenuating potential that is proposed to be due to the synergistic actions of its bioactive molecules. Further studies to explore the effects of Miet and its bioactive molecules as an adjuvant therapy with low dose anticancer drugs are warranted, which may lead to a new area of research.

Ex vivo, in vitro, and in silico approaches to unveil the mechanisms underlying vasorelaxation effect of Mentha Longifolia (L.) in porcine coronary artery.

OBJECTIVE: Mentha (M.) longifolia (L.) is traditionally used for various ailments. The current study was intended to explore the underlying vasorelaxation mechanisms of M. longifolia. MATERIAL AND METHODS: Aqueous-methanol extract from the aerial parts of M. longifolia was prepared and subjected to activity-guided fractionation. The vasorelaxant activity was performed using porcine coronary arteries with intact and denuded endothelium. In-vitro PDE inhibitory activity of the active fraction was carried out using the radio-enzymatic assay. The active fraction was also subjected to GCMS. Docking and molecular dynamic simulation studies were also performed RESULT: We had observed that aqueous-methanolic extract induced relaxation in the coronary artery in a dose-dependent manner when the endothelium was intact and denuded. n-butanol fraction (MLB) has produced a maximum effect, and it was selected for mechanistic studies. MLB has significantly enhanced the relaxation produced by cAMP and cGMP, elevating atrial natriuretic peptide, sodium nitroprusside, isoproterenol, and forskolin. The pre-treatment with MLB inhibited the contractile response produced by KCl, U46619, and CaCl2 in without endothelium rings. MLB has non-selectively inhibited the PDE isoforms. GCMS analysis of MLB has revealed the presence of menthol, thymol, and carvacrol in the active fraction. Docking and molecular dynamic simulation studies have indicated that thymol can be a competitive inhibitor for PDE1. CONCLUSION: It is postulated that an n-butanol fraction of Mentha longifolia produced endothelium-independent relaxation due to increased levels of cAMP and cGMP caused by the inhibition of various PDEs.

Biochemical Investigation of Inhibitory Activities of Plant-Derived Bioactive Compounds Against Carbohydrate and Glucagon-Like Peptide-1 Metabolizing Enzymes.

The aim of current study was to investigate the inhibitory activities of resveratrol and taxifolin against α-amylase, α-glucosidase, and DPP-IV enzymes via in vitro analysis which was further validated by in silico studies. The analysis of molecular docking was also done to determine the binding capabilities of resveratrol and taxifolin with α-amylase, α-glucosidase, and DPP-IV enzymes. Resveratrol and taxifolin having IC50 values, 47.93 ± 5.21 µ M and 45.86 ± 3.78 µ M , respectively, showed weaker effect than acarbose (4.6 ± 1.26 µ M ) on α-amylase but showed significant effect to inhibit α-glucosidase (32.23 ± .556 µ M and 31.26 ± .556 µ M , respectively). IC50 value of resveratrol and taxifolin (5.638 ± .0016 µ M and 6.691 ± .004 µ M ) in comparison to diprotin A (IC50: 7.21 ± .021 µ M ) showed that they have significant inhibitory effect on DPP-IV enzyme. Our results illustrated that resveratrol and taxifolin have potential to prevent the metabolism of carbohydrates via inhibition of α-amylase and α-glucosidase, and prolongs metabolic function of incretin by inhibiting the enzymatic activity of DPP-IV. The results of molecular docking have also revealed that resveratrol and taxifolin have significant affinity to bind with α-amylase, α-glucosidase, and DPP-IV in comparison with standard drugs such as acarbose, miglitol, and diprotin.

Quantitative determination of creatinine from serum of prostate cancer patients by N-doped porous carbon antimony (Sb/NPC) nanoparticles.

Creatinine is an indicator of hindrance in urination and renal insufficiency. Creatinine levels are the marker of the late stages of prostate cancer. Early and sensitive detection of creatinine can reduce deaths associated with prostate cancer. In this work, nitrogen-doped porous carbon antimony (Sb/NPC) nanoparticles are fabricated to be employed as a non-enzymatic biosensor. Sb/NPC has promising redox activity and is synthesized by a two-step reaction using low-cost precursors. Electrochemical sensing by Sb/NPC is conducted for standard creatinine solutions on a three-electrodes system. Cyclic voltammetry, amperometry, and electrochemical impedance spectroscopy are used to sense creatinine. LOD and LOQ of the Sb/NPC modified electrode are 0.74 µM and 2.4 µM, respectively. This electrode system analyzes creatinine in the serum of prostate cancer patients who have elevated PSA levels. More than 90% creatinine is recovered from a spiked serum sample of a prostate cancer patient. A direct relation is observed between PSA levels and creatinine levels in prostate cancer. The developed cyclic voltammetric setup detects trace concentrations of creatinine in serum.

Phytochemical profiling, antioxidant and antiproliferation potential of Euphorbia milii var.: Experimental analysis and in-silico validation.

This study was aimed to investigate the anticancer potential of Euphorbia milii (E. milii) using an exquisite combination of phytopharmacological and advanced computational techniques. The chloroform fraction (Em-C) of E. milii methanol extract showed the highest antioxidant activity (IC50: 6.41 ± 0.99 µg/ml) among all studied fractions. Likewise, Em-C also showed significant cytotoxicity (IC50: 11.2 ± 0.8 µg/ml) when compared with that of standard compound 5-fluorouracil (5-FU) (IC50: 4.22 ± 0.6 µg/ml) against hepatocarcinoma cell line (HepG2). However, in a human cervical cancer cell line (HeLa), Em-C demonstrated a non-significant difference in cytotoxicity (22.1 ± 0.8 µg/ml) when compared with that of 5-FU (IC50: 6.87 ± 0.5 µg/ml). Furthermore, Western blot and qRT-PCR analysis revealed that the suppression of HepG2 cells was the consequence of a tremendous decrease in CDK2 and E2F1 protein expression. The GC-MS analysis of Em-C revealed the unique presence of cyclobarbital (CBT) and benzodioxole derivative (BAN) as major constituents. Furthermore, molecular docking of compounds BAN, CBT, and MBT into the binding site of different molecular targets i.e. cyclin dependent kinase 2 (CDK2), thymidylate synthase (TS), caspase 3, BCL2 and topoisomerase II was carried out. Compounds BAN and CBT have demonstrated remarkable binding affinity towards CDK2 and thymidylate synthase, respectively. Molecular dynamic simulation studies have further confirmed the finding of docking analysis, suggesting that CDK2 and TS can act as an attractive molecular target for BAN and CBT, respectively. It can be concluded that these E. milii phytoconstituents (BAN and CBT) may likely be responsible for anti-invasive activity against HepG2 cells.

BSA Binding, molecular docking and in vitro biological screening of some new 1, 2, 4-triazole heterocycles bearing azinane nucleus.

A series of new compounds (5a-q), derived from 5-(1-(4-nitrophenylsulfonyl) piperidin-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol (3) were proficiently synthesized to evaluate their biological activities. 1-(4-Nitrophenylsulfonyl) piperidine-4-carbohydrazide (2) was refluxed with phenylisothiocyanate to yield an adduct which was cyclized to compound 3 by reflux reaction with 10 % potassium hydroxide. The targeted compounds 5a-q, were synthesized by stirring alkyl/aralkyl halides (4a-q) and compound 3 in a polar aprotic solvent. 1H-NMR, 13C-NMR, EI-MS and IR spectral techniques were employed to confirm the structures of all the synthesized compounds. The compounds were biologically evaluated for BSA binding studies followed by anti-bacterial, anti-inflammatory and acetylcholinesterase (AChE) activities. The active sites responsible for the best AChE inhibition were identified through molecular docking studies. Compound 5e bearing 4-chlorobenzyl moiety found most active antibacterial and anti-inflammatory agent among the synthesized compounds. The whole library of synthesized compounds except compounds 5d and 5f was found highly active for AChE inhibition and recommended for in vivo studies so that their therapeutic applications may come in utilization.

Correction: Hesperidin improves insulin resistance via down-regulation of inflammatory responses: Biochemical analysis and in silico validation.

[This corrects the article DOI: 10.1371/journal.pone.0227637.].

Hesperidin improves insulin resistance via down-regulation of inflammatory responses: Biochemical analysis and in silico validation.

Leptin resistance and co-existing insulin resistance is considered as hallmark of diet-induced obesity. Here, we investigated therapeutic potential of hesperidin to improve leptin and insulin resistance using high fat diet (HFD)-induced obese experimental animal model. We also performed in silico studies to validate therapeutic effectiveness of hesperidin by performing protein-ligand docking and molecular dynamics simulation studies. Group 1 was identified as control group receiving vehicle only. Group 2 was marked as non-treated group receiving 60% HFD. While, other groups were treated daily with orlistat (120 mg/kg/d), hesperidin (55 mg/kg/d), combination of hesperidin (55 mg/kg/d) + orlistat (120 mg/kg/d). Hesperidin alone (P<0.001) and particularly in combination with orlistat (P<0.001), resulted in controlling the levels of HFD-altered biomarkers including random and fasting state of glycemia, leptin and insulin resistance. Similarly, hesperidin also improved the serum and tissue levels of leptin, interleukin-6 and tumor necrosis factor-alpha more significantly (P<0.05) when compared with that of orlistat. These results were found to be in accordance with the results of histopathological examination of pancreas, liver and adipose tissues. In-silico studies also proved that hesperidin binds to leptin receptor with higher affinity as compared to that of orlistat and induces the favorable variations in geometrical conformation of leptin receptor to promote its association with leptin which may lead to the cascades of reactions culminating the lipolysis of fats that may ultimately lead to cure obesity. The results of this study may be a significant expectation among the forthcoming treatment strategies for leptin and insulin resistance.

Biological activity of synthesized 5-{1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}-2-mercapto-1, 3, 4-oxadiazole derivatives demonstrated by in silico and BSA binding studies

We synthesized a series of compounds bearing pharmacologically important 1,3,4-oxadiazole and piperidine moieties. Spectral data analysis by 1H-NMR, 13C-NMR, IR and EI-MS was used to elucidate the structures of the synthesized molecules. Docking studies explained the different types of interaction of the compounds with amino acids, while bovine serum albumin (BSA) binding interactions showed their pharmacological effectiveness. Antibacterial screening of these compounds demonstrated moderate to strong activity against Salmonella typhi and Bacillus subtilis but only weak to moderate activity against the other three bacterial strains tested. Seven compounds were the most active members as acetyl cholinesterase inhibitors. All the compounds presented displayed strong inhibitory activity against urease. Compounds 7l, 7m, 7n, 7o, 7p, 7r, 7u, 7v, 7x and 7v were highly active, with respective IC50 values of 2.14±0.003, 0.63±0.001, 2.17±0.006, 1.13±0.003, 1.21±0.005, 6.28±0.003, 2.39±0.005, 2.15±0.002, 2.26±0.003 and 2.14±0.002 µM, compared to thiourea, used as the reference standard (IC50 = 21.25±0.15 µM). These new urease inhibitors could replace existing drugs after their evaluation in comprehensive in vivo studies.