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The removal of 4-nitrophenol (4NP) from aqueous solution by ozone combined with nano-ZnO was investigated in a laboratory-scale reactor in which pH of solution, ZnO dosage and initial 4-nitrophenol concentration were considered as variables. The degradation of 4-nitrophenol was determined using UV-Vis and HPLC methods. Interestingly, the degradation of 4-nitrophenol was high under acidic condition where the degradation was about 93% at initial phenol solution pH=3. It was due to aggregation of nano-ZnO particles above pH=6.5. This result was different from the case of ozonation alone, in which higher pH had positive effect on the degradation of 4-nitrophenol due to the formation of hydroxyl radical. As expected, degradation efficiency increased by increasing the nano ZnO dosage and initial 4-nitrophenol concentration. It was found that the nanosized ZnO enhanced the degradation of ozone and the catalytic ozonation enhanced the degradation of 4-nitrophenol on the surface of the nanosized ZnO. In addition, the degree of degradation was also determined indirectly through Total Organic Carbon (TOC) of the samples. Carbon mineralization of 4-nitrophenol was obtained as 13.68% and 60.34% during ozonation and nano-ZnO catalytic ozonation, respectively, after 30 min reaction, proving that combined ozonation and nano-ZnO for reduction of TOC is more efficient. Also a high degree of nitrogen mineralization during catalytic ozonation was achieved at pH= 3 (7.61 mg/L). [ABSTRACT FROM AUTHOR]

The article discusses on how multiplexed arrays enable large-scale studies. It informs that discovery programs are beginning to incorporate sophisticated hypothesis-driven research that calls for hypotheses to be tested against large sample populations. This requires high-throughput gene expression assays, for which slide-based array technology is not well equipped. Multiplexed arrays enable industrial approaches to parallel analysis of target genes across large numbers of samples while offering improved reproducibility.

Piroxicam solid depositions were prepared by means of the solvent deposition technique using different concentrations of microcrystalline cellulose as carrier material. The solvent deposition system (SDS) with drug to carrier ratio of 1:9 had a rapid dissolution rate in vitro. When this SDS was administered perorally to rats with a previous experimentally induced inflammation in their paws, it exhibited a pronounced anti-inflammatory action. X-ray diffraction and infrared (IR) spectroscopy showed no differences in the crystal state of piroxicam in SDS formulation and physical mixture of piroxicam and carrier. The increase in the dissolution rate and consequent enhancement of anti-inflammatory effect of piroxicam in SDS were attributed to the reduced particle size of drug deposited on the carrier and enhanced wettability of the particles brought about by the carrier. [ABSTRACT FROM AUTHOR]

Coagulase-negative staphylococci (CoNS) are often associated with bovine mastitis and may be resistant to antimicrobial therapy. The aim of the current study was to investigate the presence of blaZ (responsible for penicillin resistance) and mecA (responsible for methicillin resistance) genes among 108 CoNS belonging to 9 different species isolated from bovine mastitis in seven dairy herds (H1-H7). Of 108 CoNS isolates, 44 were Staphylococcus haemolyticus, 17 S. chromogenes, 11 S. epidermidis, 11 S. warneri, 11 S. cohnii, 6 S. simulans, 4 S. hominis, 3 S. capitis, and 1 S. xylosus. The blaZ was detected in 65.7% (n=71) of all Staphylococcus spp. isolates. Five isolates were positive for the presence of mecA gene (4.6%), including 2 S. hominis, 1 S. haemolyticus, 1 S. epidermidis, and 1 S. warneri. All mecA-carrying CoNS were also positive for the blaZ gene and were recovered from two studied herds (H3 and H6). Some variations were also observed in distribution of both blaZ and mecA genes between CoNS species. This study demonstrates that CoNS from bovine mastitis can be reservoirs of blaZ gene. This study also provides evidence of the presence of methicillin resistant CoNS (MR-CoNS) and emphasizes the need for their epidemiological monitoring, in order to prevent the risk of spread to human through direct contact and/or consumption of contaminated food.

Staphylococcus aureus is a major causative pathogen of clinical and subclinical mastitis of dairy domesticruminants. This agent produces a variety of extracellular toxins and virulence factors including Toxic ShockSyndrome Toxin-1 (TSST-1) which is the major cause of Toxic Shock Syndrome (TSS). In this study 58S. aureus isolates obtained from 9 dairy herds in East and West Azerbaijan provinces of Iran. The testedisolates were identified on the basis of the cultural and biochemical properties as well as by amplification ofthe aroA gene, specific to S. aureus. Isolates were also analyzed for the presence of the TSST-1 encodinggene (tst) using Polymerase Chain Reaction (PCR). tst gene 350 bp was detected in 9 (15.5%) of the totalnumber of 58 isolates. The present study revealed that the PCR amplification of the aroA gene could beused as a powerful tool for identification of S. aureus from the cases of bovine mastitis. Results also showedthat the strain of S. aureus which caused mastitis can potentially produce staphylococcal toxic shocksyndrome toxin-1. Overall, our results suggest that it is of special importance to follow the presence ofTSST-1 producing S. aureus in foodstuffs, especially for protecting the consumers from toxic shocksyndrome.

Methamphetamine, pseudoephedrine, and related drugs are among the first drugs used for the stimulation of the central nervous system. In this study, two adsorbents based on graphene oxide (GO) were synthesized and used for the analysis of methamphetamine and pseudoephedrine. The prepared nano-adsorbents based on GO in this study were coated by polyaniline (PANI) and Fe 3 O 4 /C-nanodot/GO (magnetic adsorbent). The average size of nanoparticles (GO/PANI) was 18.43 nm. The specific surface area and pore size diameter of Fe 3 O 4 /C-nanodot/GO were 22.71 m 2 g - 1 and 15.23 nm, respectively. Experimental variables affecting the extraction efficiency of the analytes such as pH of the sample solution, amount of adsorbent, extraction time, and type of eluents were investigated and optimized by response surface methodology. Under optimum conditions, GO/PANI and Fe 3 O 4 /C-nanodot/GO were considered appropriate solid phase extraction adsorbents for HPLC-based analyses of the studied drugs in human urine samples. However, GO/Fe 3 O 4 nano adsorbent (Fe 3 O 4 /C-nanodot/GO) showed superior working condition than GO/PANI. The validated proposed analytical methods can be used for the quantitative determination of methamphetamine and pseudoephedrine in actual samples., (© 2024. The Author(s).)

Purpose: L-asparaginase has been widely recognized as a critical component in the treatment of various types of lymphoproliferative disorders, since its introduction in 1960s. However, its use in some cases leads to allergic reactions rendering the continuation of treatment unfeasible. Thus, the development of L-asparaginase from alternative sources or the production of engineered enzymes have always been considered. This study aimed to produce and evaluate a novel enzyme designed based on the sequence of L-asparaginase from Escherichia coli bacteria with Y176F/S241C mutations., Methods: The Y176F/S241C mutant L-asparaginase was successfully expressed as the GST-fusion protein in E. coli , and then was subjected to affinity and size exclusion chromatography. The activity of the purified enzyme was determined based on the released ammonia as the result of substrate hydrolysis using Nessler's reagent. Chemical denaturation experiment in the presence of increasing concentration of guanidinium chloride was applied to determine the folding stability of the purified enzyme., Results: The mutant enzyme was purified with an efficiency of 77-fold but at a low recovery of 0.7%. The determined kinetic parameters Km, Vmax, kcat, specific activity and catalytic efficiency were 13.96 (mM), 2.218 (mM/min), 273.9 (min -1 ), 237.8 (IU/mg) and 19.62 (mM -1 min -1 ), respectively. Moreover, unfolding free energy determined by guanidinium chloride induced denaturation for mutated and commercial L-asparaginase enzymes were 8421 J/mol and 5274 J/mol, respectively., Conclusion: The mutant enzyme showed improved stability over the wild-type. Although the expression level and recovery were low, the mutant L-asparaginase demonstrated promising activity and stability, with potential clinical and industrial applications., Competing Interests: The authors declare no conflict of interest, (©2024 The Author (s).)

Psychological disorders and dramatic social problems are serious concerns regarding the abuse of amphetamine and its stimulant derivatives worldwide. Consumers of such drugs experience great euphoria along with serious health problems. Determination and quantification of amphetamine-type stimulants are indispensable skills for clinical and forensic laboratories. Analysis of low drug doses in bio-matrices necessitates applications of simple and also effective preparation steps. The preparation procedures not only eliminate adverse matrix effects, but also provide reasonable clean-up and pre-concentration benefits. The current review presents different methods used for sample preparation of amphetamines from urine as the most frequently used biological matrix. The advantages and limitations of various sample preparation methods were discussed focusing on the miniaturized methods.

The uremic toxin indoxyl sulfate (IS) has been related to the development of various medical conditions notably chronic kidney disease (CKD). Hence, quantification of this biomarker in biological fluids may be a diagnostic tool to evaluate renal system functionality. Numerous analytical methods including liquid chromatography, gas chromatography, spectroscopy, and electrochemical techniques have since been used to analyze IS in different biological fluids. The current review highlights the relevant studies that assessed IS with a special focus on sample preparation, which is essential to reduce or eliminate the effect of endogenous components from the matrix in bioanalysis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Multi target directed ligands (MTDLs) are one of the promising tools for treatment of complex disease like Alzheimer's disease (AD). In this study, using rational design, we synthesized new 15 hybrids of the s-triazine, isatin and aniline derivatives as anti- AD compounds. The design was as way as that new compounds could had anti cholinesterase (ChE), antioxidant and biometal chelation ability. In vitro biological evaluation against ChE enzymes showed that these molecules were excellent inhibitors with IC 50 values ranging from 0.2 nM to 734.5 nM for acetylcholinesterase (AChE), and 0.02 μM to 1.92 μM for butyrylcholinesterase (BChE). Among these compounds, 8 l with IC 50 AChE  = 0.7 nM, IC 50 BChE  = 0.09 μM and 8n with IC 50 AChE  = 0.2 nM, IC 50 BChE  = 0.03 μM were the most potent compounds. In silico studies showed that these molecules had key and effective interactions with the corresponding enzymes residues. The molecules with hydroxyl group on aniline moiety had also good antioxidant activity with EC 50 values ranging from 64.2 μM to 103.6 μM. The UV-Vis spectroscopy study revealed that molecule 8n was also able to chelate biometals such as Zn 2+ , Cu 2+ and Fe 2+ properly. It was concluded that these molecules could be excellent lead compounds for future studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

There is a strong relationship between the dysregulation of epidermal growth factor receptor (EGFR) and the development of epithelial-derived cancers. Therefore, EGFR has usually been considered the desired target for gene therapy. Here, we propose an approach for targeting EGFR-expressing cells by phage particles capable of displaying EGF and GFP as tumor-targeting and reporting elements, respectively. For this purpose, the superfolder GFP-EGF (sfGFP-EGF) coding sequence was inserted at the N-terminus of the pIII gene in the pIT 2 phagemid. The capability of the constructed phage to recognize EGFR-overexpressing cells was monitored by fluorescence microscopy, fluorescence-activated cell sorting (FACS), and cell-based ELISA experiments. FACS analysis showed a significant shift in the mean fluorescence intensity (MFI) of the cells treated with phage displaying sfGFP-EGF compared to phage displaying only sfGFP. The binding of phage displaying sfGFP-EGF to A-431 cells, monitored by fluorescence microscopy, indicated the formation of the sfGFP-EGF-EGFR complex on the surface of the treated cells. Cell-based ELISA experiments showed that phages displaying either EGF or sfGFP-EGF can specifically bind EGFR-expressing cells. The vector constructed in the current study has the potential to be engineered for gene delivery purposes as well as cell-based imaging for tumor detection., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

A rapid and efficient analytical method was established to quantify indoxyl sulfate (IS) in plasma through extraction technique with a deep eutectic solvent (DES) and spectrofluorimetric method. DES (choline chloride: urea) was mixed with plasma samples for the extraction of IS, followed by the addition of dipotassium hydrogen phosphate (K 2 HPO 4 ) solution to form an aqueous two-phase system. The fluorescence intensity of IS which was first extracted to the DES-rich-phase and then back-extracted into the salt-rich-phase, was measured by spectrofluorimetric method. Some key factors such as pH, centrifugation speed and time, the volume ratio of DES/salt, and salt concentration were optimized. Under the optimized conditions, the suggested method had a dynamic range between 20 and 160 µg/mL with a coefficient of determination (R 2 ) of 0.99. Precision (relative standard deviation) was less than 15% and accuracy (% relative recovery) was ± 15% at the nominal concentration level. In addition, results showed that IS levels in real samples were higher than 40 µg/mL which was compatible with reported IS levels in end-stage renal disease (ESRD) patients. Overall, all the results reflect the fact that the presented analytical method can potentially be used for the determination of IS in real plasma samples., (© 2024. The Author(s).)

Amphetamines, as psychoactive drugs, are extensively abused in society and cause serious mental and physical disorders among young people. Furthermore, the extremely euphoric and excited sense of stimulant consumption leads to dramatic social problems. Determination of various analytes and related metabolites in the complex biological matrices at trace levels has made sample preparation an indispensable part of forensic sciences. According to the problems above, providing high sensitivity, solving some analytical problems like matrix effects in LCMS-MS, and needing a cleaner extract are remarkable aspects of novel sample preparation methods in drug analysis. Application of nanotechnology and carbon-based nanocomposites seems to bring the above properties in developed and novel sample preparation methods. This review will try to provide an overview of different carbonic nano adsorbents used in sample preparation methods of amphetamines and discuss their superiority over the other nanomaterials., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs) constitute an important class of pharmaceuticals acting on cyclooxygenase COX-1 and COX-2 enzymes. Due to their numerous severe side effects, it is necessary to search for new selective, safe, and effective anti-inflammatory drugs. In silico design of novel therapeutics plays an important role in nowadays drug discovery pipelines. In most cases, the design strategies require the use of molecular docking calculations. The docking procedure may require case-specific condition for a successful result. Additionally, many different docking programs are available, which highlights the importance of identifying the most proper docking method and condition for a given problem., Methods: In the current work, the performances of five popular molecular docking programs, namely, GOLD, AutoDock, FlexX, Molegro Virtual Docker (MVD) and Glide to predict the binding mode of co- crystallized inhibitors in the structures of known complexes available for cyclooxygenases were evaluated. Furthermore, the best performers, Glide, AutoDock, GOLD and FlexX, were further evaluated in docking-based virtual screening of libraries consisted of active ligands and decoy molecules for cyclooxygenase enzymes and the obtained docking scores were assessed by receiver operating characteristics (ROC) analysis., Results: The results of docking experiments indicated that Glide program outperformed other docking programs by correctly predicting the binding poses (RMSD less than 2 Å) of all studied co-crystallized ligands of COX-1 and COX-2 enzymes (i.e., the performance was 100%). However, the performances of the other studied docking methods for correctly predicting the binding poses of the ligands were between 59% to 82%. Virtual screening results treated by ROC analysis revealed that all tested methods are useful tools for classification and enrichment of molecules targeting COX enzymes. The obtained AUCs range between 0.61-0.92 with enrichment factors of 8 - 40 folds., Conclusion: The obtained results support the importance of choosing appropriate docking method for predicting ligand-receptor binding modes, and provide specific information about docking calculations on COXs ligands., Competing Interests: Authors declare no conflict of interests., (© 2024 The Author(s).)

Background: Histone deacetylase inhibitors (HDACIs) are important as anticancer agents. Objective: This study aimed to investigate some key structural features of HDACIs via the design, synthesis and biological evaluation of novel benzamide-based derivatives. Methods: Novel structures, designed using a molecular modification approach, were synthesized and biologically evaluated. Results: The results indicated that a subset of molecules with CH 3 /NH 2 at R 2 position possess selective antiproliferative activity. However, only those with an NH 2 group showed HDACI activity. Importantly, the shorter the molecule length, the stronger HDACI. Among all, 7j was the most potent HDAC1-3 inhibitor and antiproliferative compound. Conclusion: The results of the present investigation could provide valuable structural knowledge applicable for the development of the HDACIs and benzamide-based antiproliferative agents in the future.

Purpose: Medical usage of L-asparaginase (ASNase), the first-line of acute lymphoblastic leukemia treatment, is linked to allergic responses and toxicities, which necessitates the development of new bio-better ASNases. The aim of the current study was in silico design of a novel ASNase with predicted improved enzymatic properties using strategies encompassing sequence-function analysis of known ASNase mutants. Additionally, current study aimed to show that the new enzyme is active., Methods: Based on 21 experimentally reported mutations for ASNase, a virtual library of mutated enzymes with all 7546 possible combinations of up to 4 mutations was generated. Three-dimensional models of proposed mutant enzymes were built and their in silico stabilities were calculated. The most promising mutant was selected for preparing a genetic construct suitable for expression of the designed ASNase in bacterial cells., Results: Computational study predicted that Y176F/S241C double mutation of Escherichia coli ASNase may increase its folding stability. The designed ASNase was expressed in two different E. coli strains (Origami B(DE3) and BL21(DE3)pLysS) and then the soluble fractions prepared from the cell lysates of the host cells were used in enzyme activity assay. Results showed that enzyme activity of soluble fraction from Origami (95.4 ± 7.5 IU/0.1 mL) was four times higher than that of soluble fraction from pLysS (25.8 ± 2.5 IU/0.1 mL)., Conclusion: A novel functional double mutant ASNase with predicted improved enzymatic properties was designed and produced in E. coli. The results of the current study suggest a great commercial potential for the identified enzyme in pharmaceutical and industrial applications., Competing Interests: The authors declare no conflict of interest., (©2023 The Authors.)

Purpose: Exosomes are natural nanoparticles that participate in intercellular communication through molecular transport. Recently, due to their membrane vesicular structure and surface proteins, exosomes have been used extensively in the research field of drug delivery. Osteoporosis is an inflammation in which the cellular balance of bone tissue is disturbed that reduces bone density and making bone prone to abnormal fractures with small amount of force. Utilizing estrogen is one of the main therapeutic strategies for osteoporosis. Despite the positive effects of estrogen on bone tissue, changes in the natural estrogen levels of the body can cause a number of diseases such as different types of cancer. Therefore, designing a therapeutic system which controls more accurate tissue targeting of estrogen seems to be a rational and promising practical approach., Methods: In this study, bone marrow mesenchymal stem cells (BMMSCs)-derived exosomes were loaded by estradiol using two different methods of drug loading, namely incubation and sonication methods and then the survival effects of the drug loaded exosomes on BMMSCs was investigated., Results: Examination of size, shape, and surface factors of exosomes in different states (pure exosomes and drug-loaded exosomes) showed that the round morphology of exosomes was preserved in all conditions. However, the particles size increased significantly when loaded by sonication method. The increased survival of BMMSCs was noted with estradiol-loaded exosomes when compared to the control group., Conclusion: The results suggest that estradiol-loaded exosomes have potential to be used as nano-drug carriers in the treatment of osteoporosis., Competing Interests: The authors declare that they have no conflict of interest., (©2023 The Authors.)

Indanone derivatives containing meta/para-substituted aminopropoxy benzyl/benzylidene moieties were designed based on the structures of donepezil and ebselen analogs as the cholinesterase inhibitors. The designed compounds were synthesized and their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities were measured. Inhibitory potencies (IC 50 values) for the synthesized compounds ranged from 0.12 to 11.92 μM and 0.04 to 24.36 μM against AChE and BChE, respectively. Compound 5 c showed the highest AChE inhibitory potency with IC 50 value of 0.12 μM, whereas the highest BChE inhibition was achieved by structure 7 b (IC 50 =0.04 μM). Structure-activity relationship (SAR) analysis revealed that there is no significant difference between meta and para-substituted derivatives in AChE and BChE inhibition. However, the most potent AChE inhibitor 5 c belongs to meta-substituted compounds, while the most active BChE inhibitor is para-substituted derivative 7 b. The order of enzyme inhibition potency based on the substituted amine group is dimethyl amine>piperidine>morpholine. Compounds containing C=C linkage are more potent AChE inhibitors than the corresponding saturated structures. Molecular docking studies indicated that 5 c interacts with AChE in a very similar way to that observed experimentally for donepezil. The introduced indanone-aminopropoxy benzylidenes could be used in drug-discovery against Alzheimer's disease., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

A graphene oxide-based aerogel was synthesized and applied to the extraction and the determinations with the high-performance liquid chromatography-ultraviolet detector. After the characterization of the produced graphene-aerogel, it was utilized as a dispersive solid-phase extraction sorbent for risperidone extraction from plasma samples. Aerogels are materials with a large surface area-to-mass ratio and plenty of core with functional groups which can easily attach to the analytes to extract them to the second phase. The suggested method determined risperidone in plasma samples in the wide dynamic range from 20 ng/ml to 3 μg/ml. The limits of detection and quantification of the developed method were calculated as 2.4 and 8.2 ng/ml, respectively. As a novel feature, the developed method has no need to precipitate plasma proteins, improving the analytical performance of the analysis. Also, for the first time, the produced materials were utilized for the extraction of risperidone from the plasma samples. The obtained results revealed that the developed approach could be employed as an accurate method for the quantification of risperidone in real plasma samples., (© 2023 Wiley-VCH GmbH.)

Purpose: Teduglutide is the first and only FDA-approved drug for long-term treatment of short bowel syndrome (SBS). The current study aimed to present an approach for production of teduglutide using recombinant DNA technology., Methods: The coding gene for teduglutide was cloned into pGEX-2T vector, where coding sequence for factor Xa cleavage site was added between GST and teduglutide coding genes. The GST-teduglutide protein was overexpressed in E. coli BL21 (DE3) strain and affinity purified using glutathione sepharose affinity column., Results: On-column proteolytic activity of factor Xa followed by size exclusion chromatography resulted in the pure teduglutide. Circular dichroism (CD) spectropolarimetry showed that the produced teduglutide folds into mainly α-helical structure (>50%), as expected. In mass spectroscopy analysis, the fragments of teduglutide resulted by cyanogen bromide cleavage as well as those expected theoretically due to mass fragmentation were identified. The functionality of the produced peptide was evaluated by measuring its proliferative effect on Caco2 intestinal epithelial cells, and the results indicated that produced teduglutide induces cell proliferation by 19±0.30 and 33±7.82 % at 1.21 and 3.64 µM concentrations, respectively, compared to untreated cells., Conclusion: Teduglutide was successfully expressed and purified and its functionality and structural integrity were confirmed by in vitro experiments. We believe that the experimental-scale method presented in the current study can be useful for pilot-scale and also industrial-scale production of teduglutide., Competing Interests: The authors declare no conflict of interest., (©2023 The Authors.)

In the current study, bismuth ferrite nano-sorbent was synthesized and utilized as a sorbent for the dispersive solid-phase extraction of methylprednisolone from exhaled breath samples. The size and morphology of the nano-sorbent were characterized by X-ray diffraction analysis and scanning electron microscopy. Following its desorption with acetonitrile, methylprednisolone was quantified by a high-performance liquid chromatography-ultraviolet detector. Factors affecting the extraction of methylprednisolone were optimized. Under optimized experimental conditions, a linear relationship between the analytical signals and methylprednisolone concentration was obtained in the range of 0.001-0.2 μg mL -1 for exhaled breath condensate samples and 0.002-0.4 μg per filter for filter samples. A pre-concentration factor of 6.4-fold, corresponding to an extraction recovery of 96.0%, was achieved. The validated method was applied for the determination of methylprednisolone in real samples taken from the exhaled breath of COVID-19 patients under mechanical ventilation., Competing Interests: The author(s) declare that they have no competing interests., (This journal is © The Royal Society of Chemistry.)

Multiple sclerosis (MS) is a neurological disease that leads to severe physical and cognitive disabilities. Drugs used in the treatment of MS vary from small synthetic molecules to large macromolecules such as antibodies. Sphingosine 1-phosphate receptor modulators are frequently used for the treatment of MS. These medicines prevent the egress of lymphocytes from secondary lymphoid organs leading to immune system suppression. Currently, four S1PR modulators are on the market and several potential drug candidates are in clinical trials for the treatment of MS. These compounds differ in chemical structure, adverse effects, and efficacy points of view. The current article reviews the latest studies on S1PR1 modulators and compares them with other MS drugs in terms of efficacy, tolerability, and safety. A special focus was dedicated to discussing the structure-activity relationships of these compounds and performing a three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis to gain better insight into the ligand-receptor interaction mode., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Purpose: Drug repurposing is an approach successfully used for discovery of new therapeutic applications for the existing drugs. The current study was aimed to use the combination of in silico methods to identify FDA-approved drugs with possible S1P 1 agonistic activity useful in multiple sclerosis (MS). Methods: For this, a 3D-QSAR model for the known 21 S1P 1 agonists were generated based on 3D-QSAR approach and used to predict the possible S1P 1 agonistic activity of FDA-approved drugs. Then, the selected compounds were screened by docking into S1P 1 and S1P 3 receptors to select the S1P 1 potent and selective compounds. Further evaluation was carried out by molecular dynamics (MD) simulation studies where the S1P 1 binding energies of selected compounds were calculated. Results: The analyses resulted in identification of cobicistat, benzonatate and brigatinib as the selective and potent S1P 1 agonists with the binding energies of -85.93, -69.77 and -67.44 kcal. mol -1 , calculated using MM-GBSA algorithm based on 50 ns MD simulation trajectories. These values are better than that of siponimod (-59.35 kcal mol -1 ), an FDA approved S1P 1 agonist indicated for MS treatment. Furthermore, similarity network analysis revealed that cobicistat and brigatinib are the most structurally favorable compounds to interact with S1P 1 . Conclusion: The findings in this study revealed that cobicistat and brigatinib can be evaluated in experimental studies as potential S1P 1 agonist candidates useful in the treatment of MS., Competing Interests: The authors declare no conflict of interest., (©2023 The Authors.)

Lead optimization as a bottleneck in the process of drug discovery is conducted to tackle problems associated with poor pharmacokinetics, continuous emergence of drugresistance, adverse side effects and drug-drug interactions of known pharmaceuticals. Due to the intensive application of multi-targeted tyrosine kinase inhibitors (MTKI) in various pathological conditions, optimization of their structures has always been the focus of intensive medicinal chemistry research efforts. The current review portrays the application of scaffold hopping, bioisosterism, structure-based, and hybrid-based drug design methods in the optimization of lead compounds aiming to enhance their usefulness as novel drugs. Then, the review proceeds with examples of structural modifications carried out, particularly on multi-targeted drugs already available on the market. The demonstrated examples cover structural modifications on 7 well-known drugs during the last twenty years. The application of the above-mentioned strategies has led to the generation of 52 new multitargeted tyrosine kinase inhibitors. Most of the optimized compounds showed improved properties compared to their parent lead compound. The rationales behind the applied modifications and the achieved outcomes were discussed to present practical examples to the researchers engaged in the area., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Histone deacetylases (HDACs) are one of the essential epigenetic targets in cancer treatment. These enzymes play key roles in post-translation modification (PTM) and gene expression, and consequently, their inhibitors are about to find their place in pharmacotherapy. Most of the currently approved HDAC inhibitors (HDACIs) are wide-spectrum with poor clinical outcomes and numerous side effects. Therefore, new generations of HDAC-based chemotherapeutics with better clinical outcomes are emerging, e.g., isoform-selective inhibitors, multitargeted HDACIs, as well as HDAC degraders., Aim: The review intended to introduce drug design approaches which were used for designing novel agents which can be beneficial in the process of finding new and more effective HDACI-based therapeutics., Methods: PubMed and other databases were searched for literature regarding the structure-function of HDAC isoforms, and strategies used to design HDAC inhibitors. Also, all clinical trials available from the ClinicalTrials site for years 2021-2022 were investigated., Key Findings: It is expected that the future of drug discovery projects in HDAC field will concentrate mostly on issues such as isoform-selectivity, multitargeted HDAC inhibitors and HDAC degraders. Deeper knowledge of the 3D structure of HDACs complexed with inhibitors and extensive delineation of biological roles of HDACs are needed for efficient investigations leading to the discovery of novel potent inhibitors., Significance: Histone deacetylases (HDACs) are one of the important epigenetic targets in cancer treatment drug discovery. Comprehending the structure of HDAC isoforms along with applied drug design strategies can inspire new ideas., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

The profound impact of in silico studies for a fast-paced drug discovery pipeline is undeniable for pharmaceutical community. The rational design of novel drug candidates necessitates considering optimization of their different aspects prior to synthesis and biological evaluations. The affinity prediction of small ligands to target of interest for rank-ordering the potential ligands is one of the most routinely used steps in the context of virtual screening. So, the end-point methods were employed for binding free energy estimation focusing on evaluating simulation time effect. Then, a set of human aldose reductase inhibitors were selected for molecular dynamics (MD)-based binding free energy calculations. A total of 100[Formula: see text]ns MD simulation time was conducted for the ligand-receptor complexes followed by prediction of binding free energies using MM/PB(GB)SA and LIE approaches under different simulation time. The results revealed that a maximum of 30[Formula: see text]ns simulation time is sufficient for determination of binding affinities inferred from steady trend of squared correlation values (R 2 ) between experimental and predicted [Formula: see text]G as a function of MD simulation time. In conclusion, the MM/PB(GB)SA algorithms performed well in terms of binding affinity prediction compared to LIE approach. The results provide new insights for large-scale applications of such predictions in an affordable computational cost.

Purpose: Today, the discovery of novel and effective chemotherapeutic compounds is the main challenge in cancer therapy. In recent years, the anti-tumoral activity of natural naphthoquinone juglone (JUG), present in different parts of walnut trees, has received considerable interest. The purpose of the current study was to prepare and evaluate the in vitro antiproliferative activity of JUG-loaded bovine serum albumin nanoparticles (JUG-BSA NPs). Methods: BSA NPs and JUG-BSA NPs were prepared using the desolvation technique. The NPs were characterized for their particle size (PS), zeta potential (ZP), drug loading (DL) capacity and encapsulation efficiency (EE). The anti-proliferative activity of JUG-BSA NPs was evaluated on A431 and HT29 cancer cell lines using cellular uptake and MTT assays. Results: The PS and ZP values of JUG-BSA NPs were 85 ± 6.55 nm and -29.6 mV, respectively. The DL capacity and EE were 3.7% to 5% and 50.4% to 94.6%, respectively. The cytotoxicity of JUG-BSA NPs was significantly less on both cultured A431 and HT29 cells at the studied concentrations when compared to free JUG. However, the effect was not very substantial, particularly at high levels. Conclusion: In conclusion, BSA NPs can be used as a suitable and safe carrier for the delivery of JUG, a cytotoxic hydrophobic natural compound., Competing Interests: The authors declare that there is no conflict of interest., (©2022 The Authors.)

Histone deacetylases (HDACs) are overexpressed in cancer, and their inhibition shows promising results in cancer therapy. In particular, selective class I HDAC inhibitors such as entinostat are proposed to be more beneficial in breast cancer treatment. Computational drug design is an inevitable part of today's drug discovery projects because of its unequivocal role in saving time and cost. Using three HDAC inhibitors trichostatin, vorinostat, and entinostat as template structures and a diverse fragment library, all synthetically accessible compounds thereof (∼3200) were generated virtually and filtered based on similarity against the templates and PAINS removal. The 298 selected structures were docked into the active site of HDAC I and ranked using a calculated binding affinity. Top-ranking structures were inspected manually, and, considering the ease of synthesis and drug-likeness, two new structures (3a and 3b) were proposed for synthesis and biological evaluation. The synthesized compounds were purified to a degree of more than 95% and structurally verified using various methods. The designed compounds 3a and 3b showed 65-80 and 5% inhibition on HDAC 1, 2, and 3 isoforms at a concentration of 10 μM, respectively. The novel compound 3a may be used as a lead structure for designing new HDAC inhibitors.