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A novel carbazole compound, named 1-(9-ethyl-9H-carbazol-3-yl)-3-phenylurea (Cpu) was synthesized and its binding properties with protease enzymes (pepsin and trypsin) has been examined by steady-state fluorescence measurements, UV/vis absorption, infrared (FT-IR) and circular dicroism (CD) spectroscopies and also computational methods. The fluorescence experimental results indicated that the quenching mechanism of enzyme by Cpu is static process. The thermodynamic parameters (both negative ΔH/ΔS) and molecular docking results suggested that the binding of Cpu to pepsin/trypsin were driven by hydrogen bonds and van der Waals forces. Based on Förster's theory, the binding distance (r) between pepsin/trypsin and Cpu was calculated to be 3.072/2.784 nm, which implies that non-radiative energy transfer occurs from enzyme to Cpu. Furthermore, absorption, CD, and FT-IR spectral analysis provided an evidence that the presence of Cpu induced notable changes in the secondary structures and microenvironmental of both pepsin and trypsin, supporting its significant influence on these enzymes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Endocrine-disrupting chemicals (EDCs) are substances that can disrupt the normal functioning of hormones.Using aptamers, which are biological recognition elements, biosensors can quickly and accurately detect EDCs in environmental samples. However, the elucidation of aptamer structures by conventional methods is highly challenging due to their complexity. This has led to the development of three-dimensional aptamer structures based on different models and techniques. To do this, we developed a way to predict the 3D structures of the SS DNA needed for this sequence by starting with an aptamer sequence that has biosensor properties specific to bisphenol-A (BPA), one of the chemicals found in water samples that can interfere with hormones. In addition, we will elucidate the intermolecular mechanisms and binding affinity between aptamers and endocrine disruptors using bioinformatics techniques such as molecular docking, molecular dynamics simulation, and binding energies. The outcomes of our study are to compare modeling programs and force fields to see how reliable they are and how well they agree with results found in the existing literature, to understand the intermolecular mechanisms and affinity of aptamer-based biosensors, and to find a new way to make aptamers that takes less time and costs less., Competing Interests: Declaration of Competing interest The authors declare no conflict of interest, financial or otherwise., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The binding properties between vitamin B12 (vitB12, cyanocobalamin) and fibrinogen (Fib) were investigated by UV-vis absorption and steady-state/three-dimentional (3D) fluorescence spectra techniques as well as molecular docking. The experimental results showed that the intrinsic fluorescence of Fib quenched by vitB12 with static mechanism to form a non-fluorescent complex. The positive signs of thermodynamic parameters, ΔH (92.18 kJ/mol) and ΔS (433.5 J/molK), indicated that the hydrophobic forces were dominant in the binding mode. The molecular docking data were found to be in agreement with these experimental results and were confirmed by three hydrophobic interactions between the Trp430, Try390 residues of Fib and the vitamin. 3D spectra showed that fibrinogen undergoes a conformation change when it interacts with vitB12. Based on non-radiative energy transfer theory, binding distance was calculated to be 3.94 nm between donor (tryptophan residues of Fib) and acceptor (vitB12). The limit of detection (LOD) of vitB12 was calculated as 2.08 µM in the presence of fibrinogen. The relative standard deviation (RSD) of method was 4.28% for determinations (n = 7) of a vitB12 solution with the concentration of 7.80 µM., (© 2024. The Author(s).)

In this study, 2(3),9(10),16(17),23(24)-tetrakis-[( N -methyl-(1-benzylpiperidin-4-yl)oxy)phthalocyaninato]zinc(II) iodide (ZnPc-2) was synthesized and characterized using spectral methods (FT-IR, 1 H-NMR, UV-Vis and mass spectroscopy). The interaction of ZnPc-2 with DNA was investigated by using the UV/Vis titrimetric method, thermal denaturation profile, agarose gel electrophoresis and molecular docking studies. Additionally, the antidiabetic activity of ZnPc-2 was revealed spectroscopically by studying α-amylase and α-glucosidase inhibition activities. The spectroscopic results indicated that ZnPc-2 effectively binds to calf thymus-DNA (CT-DNA) with a K b value of 7.5 × 10 4 M -1 and interacts with CT-DNA via noncovalent binding mode. Gel electrophoresis results also show that ZnPc-2 binds strongly to DNA molecules and exhibits effective nuclease activity even at low concentrations. Furthermore, docking studies suggest that ZnPc-2 exhibits a stronger binding tendency with DNA than the control compounds ethidium bromide and cisplatin. Consequently, due to its strong DNA binding and nuclease activity, ZnPc-2 may be suitable for antimicrobial and anticancer applications after further toxicological tests. Additionally, antidiabetic studies showed that ZnPc-2 had both α-amylase and α-glucosidase inhibition activity. Moreover, the α-glucosidase inhibitory effect of ZnPc-2 was approximately 3500 times higher than that of the standard inhibitor, acarbose. Considering these results, it can be said that ZnPc-2 is a moderate α-amylase and a highly effective α-glucosidase inhibitor. This suggests that ZnPc-2 may have the potential to be used as a therapeutic agent for the treatment of type 2 diabetes.

This study investigates the use of nanodiamonds (ND) as a promising carrier for enzyme immobilization and compares the effectiveness of immobilized and native enzymes. Three different enzyme types were tested, of which Rhizopus niveus lipase (RNL) exhibited the highest relative activity, up to 350 %. Under optimized conditions (1 h, pH 7.0, 40 °C), the immobilized ND-RNL showed a maximum specific activity of 0.765 U mg -1 , significantly higher than native RNL (0.505 U mg -1 ). This study highlights a notable enhancement in immobilized lipase; furthermore, the enzyme can be recycled in the presence of a natural deep eutectic solvent (NADES), retaining 76 % of its initial activity. This aids in preserving the native conformation of the protein throughout the reusability process. A test on brine shrimp revealed that even at low concentrations, ND-RNL had minimal toxicity, indicating its low cytotoxicity. The in silico molecular dynamics simulations performed in this study offer valuable insights into the mechanism of interactions between RNL and ND, demonstrating that RNL immobilization onto NDs enhances its efficiency and stability. All told, these findings highlight the immense potential of ND-immobilized RNL as an excellent candidate for biological applications and showcase the promise of further research in this field., Competing Interests: Declaration of competing interest No known financial or personal interests could have influenced the work reported in this study by the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancer is a life-threatening disease, and significant efforts are still being made to treat it. In this study, we synthesized and characterized novel hybrid molecules ( 10 - 18 ) containing hydrazone and sulfonate moieties and tested their cell growth inhibitory effect on human colon cancer cells (DLD-1), human prostate cancer cells (PC3), and human embryonic kidney cells (HEK-293T) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method for 72 h. In cell culture studies, all tested hybrid molecules except for 12 and 13 showed significant cytotoxic activities at a micromolar level with IC 50 values in the range of 10.28-214.0 μM for the PC3 cell line and 13.49-144.30 μM for the DLD-1 cell line. Compounds 4 (10.28 μM) and 5 (11.22 μM) demonstrated the highest cytotoxicity against the PC3 cell line. Against the DLD-1 cell line, compounds 1 (22.53 μM), 4 (13.49 μM), 5 (19.33 μM), 6 (17.82 μM), 8 (24.71 μM), 9 (17.56 μM), and 10 (17.90 μM) in the series showed anticancer activity at lower micromolar levels compared to cisplatin (26.70 μM). Moreover, the study was handled computationally, and molecular docking studies were performed for compounds 1 , 4 , and 5 for PC3-FAK and PC3-Scr and compounds 4 , 6 , and 9 for the DLD-1-TNKS target. In this study, compound 4 was found to be the most effective and promising molecule for both targets., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The synthesis and biological assessment of novel multi-functionalized pyrrolidine-containing benzenesulfonamides were reported along with their antimicrobial, antifungal, CAs inhibition, and AChE inhibition as well as DNA-binding effects. The chemical structure of the compounds was elucidated by using FTIR, NMR, and HRMS. Compound 3b , which had Ki values of 17.61 ± 3.58 nM (hCA I) and 5.14 ± 0.61 nM (hCA II), was found the be the most potent CAs inhibitor. Compounds 6a and 6b showed remarkable AChE inhibition effects with Ki values 22.34 ± 4.53 nM and 27.21 ± 3.96 nM in comparison to tacrine. Compounds 6a-6c had moderate antituberculosis effect on M. tuberculosis with a MIC value of 15.62 μg/ml. Compounds had weaker antifungal and antibacterial activity in the range of MIC 500 - 62.5 μg/ml against standard bacterial and fungal strains. Besides these above, molecular docking studies were performed to examine and evaluate the interaction of the remarkable compounds ( 3b, 6a and 6b ) against the current enzymes (CAs and AChE). Novel compounds gained interest in terms of enzyme inhibitory potencies. Therefore, the most potent enzyme inhibitors may be considered lead compounds to be modified for further research.Communicated by Ramaswamy H. Sarma.

N-substitued anthranilic acid derivatives are commonly found in the structure of many biologically active molecules. In this study, new members of hydrazones derived from anthranilic acid (1-15) were synthesized and investigated their effect on some metabolic enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase (α-Gly). Results indicated that all the molecules exhibited potent inhibitory effects against all targets as compared to the standard inhibitors, revealed by IC 50 values. K i values of compounds for AChE, BChE, and α-Gly enzymes were obtained in the ranges 66.36 ± 8.30-153.82 ± 13.41, 52.68 ± 6.38-113.86, and 2.13 ± 0.25-2.84 nM, respectively. The molecular docking study was performed for the most active compounds to the determination of ligand-enzyme interactions. Binding affinities of the most active compound were found at the range of -9.70 to -9.00 kcal/mol for AChE, -11.60 to -10.60 kcal/mol for BChE, and -10.30 to -9.30 kcal/mol for α-Gly. Molecular docking simulations showed that the novel compounds had preferential interaction with AChE, BChE, and α-Gly. Drug-likeness properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analyzes of all synthesized compounds (1-15) were estimated and their toxic properties were evaluated as well as their therapeutic properties. Moreover, molecular dynamics simulations were carried out to understand the accuracy of the most potent derivatives of docking studies., (© 2023 Wiley Periodicals LLC.)

Oxazolidinones are used as various potent antibiotics, in organisms it acts as a protein synthesis inhibitor, focusing on an initial stage that encompasses the tRNA binding process. Novel intramolecular aza-Michael reactions devoid of metal catalysts have been introduced in an oxazolidone synthesis pathway, different from α,β-unsaturated ketones. Oxazolidinone derivatives were tested against acetylcholinesterase (AChE), carbonic anhydrase I and II (hCA I and hCA II) enzymes. All the synthesized compounds had potent inhibition effects with Ki values in the range of 13.57 ± 0.98 - 53.60 ± 6.81 µM against hCA I and 9.96 ± 1.02 - 46.35 ± 3.83 µM against hCA II in comparison to the acetazolamide (AZA) ( Ki  = 50.46 ± 6.17 µM for hCA I) and for hCA II ( Ki = 41.31 ± 5.05 µM). Also, most of the compounds demonstrated potent inhibition ability towards AChE enzyme with K i values 78.67-231.75 nM and compared to tacrine (TAC) as standard clinical inhibitor ( Ki  = 142.48 nM). Furthermore, ADMET analysis and molecular docking were calculated using the AChE, hCA I and hCA II enzyme proteins to correlate the data with the experimental data. In this work, recent applications of a stereoselective aza-Michael reaction as an efficient tool for of nitrogen-containing heterocyclic scaffolds and their useful to pharmacology analogs are reviewed and summarized.Communicated by Ramaswamy H. Sarma.

This report presents the synthesis and characterization of a range of benzimidazolium salts featuring 3-cyanopropyl groups on the 1 st nitrogen atom and varied alkyl groups on the 3 rd nitrogen atom within the benzimidazole structure. Benzimidazolium salts were synthesized by N-alkylation of 1-alkyl benzimidazole with 3-cyanopropyl-bromide. The new salts were characterized by 1 H and 13 C-NMR, FT-IR spectroscopic and elemental analysis techniques. In this study, the enzyme inhibition abilities of seven nitrile substituted benzimidazolium salts were investigated against acetylcholinesterase (AChE) and carbonic anhydrase isoenzymes I and II (hCA I and hCA II). They showed a highly potent inhibition effect on AChE, hCA I and hCA II (K i values are in the range of 26.71-119.09 nM for AChE, 19.77 to 133.68 nM for hCA I and 13.09 to 266.38 nM for hCA II). Reflecting the binding mode of the synthesized cyanopropyl series, the importance of the 2,3,5,6-tetramethylbenzyl, 3-methylbenzyl and 3-benzyl groups for optimal interactions with target proteins, evaluated by molecular docking studies. At the same time, the docking findings support the inhibition constants (K i ) values of the related compounds in this study. Potential compounds were also evaluated by their pharmacokinetic properties were predicted., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Herein, we present how to synthesize thirteen new 1-(4-acetylphenyl)-3-alkylimidazolium salts by reacting 4-(1-H-imidazol-1-yl)acetophenone with a variety of benzyl halides that contain either electron-donating or electron-withdrawing groups. The structures of the new imidazolium salts were conformed using different spectroscopic methods ( 1 H NMR, 13 C NMR, 19 F NMR, and FTIR) and elemental analysis techniques. Furthermore, these compounds' the carbonic anhydrase (hCAs) and acetylcholinesterase (AChE) enzyme inhibition activities were investigated. They showed a highly potent inhibition effect toward AChE and hCAs with K i values in the range of 8.30 ± 1.71 to 120.77 ± 8.61 nM for AChE, 16.97 ± 2.04 to 84.45 ± 13.78 nM for hCA I, and 14.09 ± 2.99 to 69.33 ± 17.35 nM for hCA II, respectively. Most of the synthesized imidazolium salts appeared to be more potent than the standard inhibitor of tacrine (TAC) against AChE and Acetazolamide (AZA) against CA. In the meantime, to prospect for potential synthesized imidazolium salt inhibitor(s) against AChE and hCAs, molecular docking and an ADMET-based approach were exerted., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Herein, eight new NHC-based selenourea derivatives were synthesized and characterized by using spectroscopic method ( 1 H, 19 F, and 13 C NMR, FT-IR), and elemental analysis techniques. These compounds were synthesized by mixing benzimidazolium salts, potassium carbonate, and selenium powder in ethyl alcohol. Additionally, the molecular and crystal structures of the three compounds ( 1c , 2b , and 2c ) were determined using the single-crystal x-ray diffraction (XRD) method. Diffraction analysis demonstrated the partial carbon-selenium double-bond character of these compounds. All compounds were determined to be highly potent inhibitors for AChE and XO enzymes. The IC 50 values for the compounds were found in the range of 0.361-0.754 μM for XO and from 0.995 to 1.746 μM for AChE. The DNA binding properties of the compounds were investigated. These compounds did not have a remarkable DNA binding property. Also, DPPH radical scavenging activities of the compounds were also investigated. Compounds ( 1c ), ( 2a ), ( 3a ), and ( 3b ) exhibited more pronounced DPPH radical scavenging activity when compared to other compounds. Docking studies were applied by using AutoDock 4 to determine interaction mechanism of the selected compounds ( 1a ), ( 1b ), and ( 3b ). The compound ( 1b ) has good binding affinity (-9.78 kcal/mol) against AChE, and (-6.86 kcal/mol) for XO target. Drug similarity properties of these compounds compared to positive controls were estimated and evaluated by ADMET analysis. Furthermore, molecular dynamics simulations have been applied to understand the accuracy of docking studies. These findings and the defined compounds could be potential candidates for the discovery and progress of effective medicine(s) for AChE and XO in the future.Communicated by Ramaswamy H. Sarma.

A series of xanthene-based thiazoles was synthesized and characterized by different scpectroscopic methods, i.e. Proton nuclear magnetic resonance ( 1 H NMR), carbon nuclear magnetic resonance ( 13 C NMR), infrared spectroscopy, carbon hydrogen nitrogen analysis, and X-ray crystallography. The inhibition potencies of 18 newly synthesized thiazole derivatives were investigated on the activities of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-amylase (α-Amy), and α-glycosidase (α-Gly) enzymes in accordance with their antidiabetic and anticholinesterase ability. The synthesized compounds have the highest inhibition potential against the enzymes at low nanomolar concentrations. Among the 18 newly synthesized molecules, 3b and 3p were superior to the known commercial inhibitors of the enzymes and have a much more effective inhibitory potential, with IC 50 : 2.37 and 1.07 nM for AChE, 0.98 and 0.59 nM for BChE, 56.47 and 61.34 nM for α-Gly, and 152.48 and 124.84 nM for α-Amy, respectively. Finally, the optimized 18 compounds were subjected to molecular docking to describe the interaction between thiazole derivatives and AChE, BChE, α-Amy, and α-Gly enzymes in which important interactions were monitored with amino acid residues of each target enzyme., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

In this study, the novel 4-(4-Aminopyrimidin-2-ylthio) phthalonitrile ( 1) as starting material was synthesized and its 3D structure was verified by the single crystal X-ray diffraction experiment. Then, its peripherally tetra-substituted phthalocyanines ( 2,3) and the methylated derivatives ( 2a,3a) containing pyrimidine derivative were synthesized. All these newly synthesized compounds were characterized with various spectroscopic methods such as UV-Vis, FT-IR, 1 H-NMR, 13 C-NMR and MALDI-TOF MS by obtaining satisfactory results. In addition, these novel phthalocyanines effectively inhibited acetylcholinesterase enzyme, with K i values in the range of 10.43 ± 2.38 to 41.70 ± 9.32 µM. For the related enzyme, the IC 50 values were obtained in the range of 11.68 to 44.28 µM. For α-glycosidase enzyme the most effective K i values of ( 3a) and ( 2) were with K i values of 92.87 ± 10.70 and 95.18 ± 17.83 µM, respectively. Indeed, the most potent phthalocyanines against both enzymes were recorded for the purpose of investigating interaction modes of these complexes in the active site of the target enzyme. The cytotoxicity potential of these phthalocyanines against human breast, colon, and prostate cancers demonstrated that these compounds had normal cytotoxic effects.Communicated by Ramaswamy H. Sarma.

In this study, the therapeutic potential and phytochemical composition of ethanolic extract of Cephalaria elazigensis var . purpurea (CE), an endemic species, were investigated. For this purpose, the antiproliferative effect of CE on the MCF-7 human breast cancer cell line was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and its effectiveness on colony formation and cell migration was analyzed with clonogenic assay and wound healing assay, respectively. In addition, the cell death detection ELISA (CDDE) assay was conducted to determine the pro-apoptotic capacity of CE. The IC 50 value of the CE was determined as 324.2 ± 14.7 µg/mL. Furthermore, upon 1000 µg/mL CE treatment, there was 4.96-fold increase in the population of cells undergoing apoptosis compared to the untreated control cells. The antioxidant activity tests were performed by DPPH free radical, ABTS cation radical, ferric-ion reducing power (FRAP) and ferrous-ion chelating power (FCAP) assays. Antioxidant activity values for the DPPH, ABTS and FRAP assays were found to be 125.6 ± 6.3, 34.09 ± 0.1 and 123.4 ± 4.2 µmol TE/mg DE, respectively. We further determined the effect of CE ethanolic extract against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. CE plays an effective inhibitory role in AChE and BuChE (AChE: IC 50 : 10.54 µg/mL, BuChE: IC 50 : 6.84 µg/mL) respectively. Further, molecular docking stuy was conducted to understand the nature of the all compound against AChE an BChE. It is revealed that α-Linolenic acid shows lowest binding energy (-7.90 kcal/mol) towards AChE, on the other side, Linoleic acid shows good binding affinity (-7.40 kcal/mol) for BChE.Communicated by Ramaswamy H. Sarma.

Background: This work contains the synthesis of seven new N-heterocyclic compounds bearing imidazole, benzimidazole, pyridine, and morpholine moieties., Objectives: We aimed to synthesize N-heterocyclic compounds for a more effective drug candidate to increase the amount of acetylcholine in synapses in Alzheimer's disease. All compounds were characterized by 1 H NMR, 13 C NMR, FTIR and elemental analysis. Enzyme inhibition activity of all compounds against acetylcholinesterase was investigated, which is an indirect treatment for Alzheimer's. Molecular docking was applied to estimate the binding energy of these compounds to the acetylcholinesterase., Methods: All compounds were synthesized from reactions of 2 equivalents of N-heterocyclic starting material and 1 equivalent of 4,4'-bis(chloromethyl)-1,1'-biphenyl. The inhibition parameters of IC 50 and K i were calculated by the spectrophotometric method. AutoDock4 was used to define the binding pose of the compounds., Results: K i values were found in the range of 80.03 ± 19.64 to 5014.98 ± 1139.60 nM for AChE as an enzyme inhibition strategy, which is an important parameter for the treatment of neurodegenerative such as Alzheimer's disease. In this study, molecular docking is exerted to predict the binding energy of heterocyclic compounds (especially 2, 3, and 5) against acetylcholinesterase enzyme. Their docking binding energies are in good agreement with experimental findings., Conclusion: These new syntheses are drugs that can be used as AChE inhibitors in Alzheimer's disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In this study, two chiral Schiff base ligands (L1 and L2) were synthesized from the condensation reaction of (S)-2-amino-3-phenyl-1-propanol with 2-hydroxybenzaldehyde and 2-hydroxy-1-naphthaldehyde as metal precursors for the preparation of transition metal complexes with Pd(II), Fe(II), Ni(II) and Cu(II). The compounds were characterized by using X-ray (for L1-Pd(II)), NMR, FT-IR, UV-Vis, magnetic susceptibility, molar conductivity, and elemental analysis. The in vitro cytotoxic effects of ligands (L1 and L2) and their metal complexes on colon cancer cells (DLD-1), breast cancer cells (MDA-MB-231) and healthy lung human cell lines were investigated by using the 3-(4,5-dimethylthiazol-2-yl)-2,5‑diphenyl tetrazolium bromide (MTT) assay. Among the synthesized compounds, L1-Pd(II) was particularly found to be the most potent anticancer drug candidate in this series with IC 50 values of 4.07, and 9.97 µM in DLD-1 and MDA-MB-231 cell lines, respectively. In addition, molecular docking results indicate that Glu122, Asn103, Ala104, Lys126, Phe114, Leu123, and Lys126 amino acids are the binding site of the colon cancer antigen protein, in which the most active complex, L1-Pd(II) can inhibit the current target., 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 © 2022 Elsevier Inc. All rights reserved.)

A series of new imidazolium salts were prepared in good yield by the reaction between 1-alkylimidazole and a variety of alkyl halides. The structures of the compounds were identified by FT-IR, 1 H NMR, and 13 C NMR spectroscopy, elemental analysis, and mass spectrometry. The crystal structure of 1b was determined by the single-crystal X-ray diffraction method. The phthalimide-tethered imidazolium salts exhibited inhibition abilities toward acetylcholinesterase (AChE) and human carbonic anhydrases (hCAs) I and II, with K i values in the range of 24.63 ± 3.45 to 305.51 ± 35.98 nM for AChE, 33.56 ± 3.71 to 218.01 ± 25.21 nM for hCA I and 17.75 ± 0.96 to 308.67 ± 13.73 nM for hCA II. The results showed that the new imidazolium salts can play a key role in the treatment of Alzheimer's disease, epilepsy, glaucoma, and leukemia, which is related to their inhibition abilities of hCA I, hCA II, and AChE. Molecular docking and in silico absorption, distribution, metabolism, excretion and toxicity studies were used to look into how the imidazolium salts interacted with the specific protein targets. To better visualize and understand the binding positions and the influence of the imidazolium salts on hCA I, hCA II, and AChE conformations, each one was subjected to molecular docking simulations., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

Five 4-hydroxyphenylethyl substituted pyridine enhanced, precatalyst, preparation, stabilization, and initiation-Pd-N-heterocyclic carbene (PEPPSI-Pd-NHC) complexes are synthesized in a straightforward way. All PEPPSI-Pd-NHC complexes were prepared by mixing 4-hydroxyphenylethyl substituted NHC precursors, palladium chloride, potassium carbonate, and potassium bromide in pyridine. All complexes were screened for human carbonic anhydrase I (hCA I) and hCA II, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase (α-Glu) inhibitory activities. The ChE inhibitory activities of the new PEPPSI-Pd-NHC complexes bearing the 4-hydroxyphenylethyl group (1a-e) against α-Glu, AChE, and BChE were determined by the Tao and Ellman methods. The results indicated that all the synthetic complexes exhibited potent inhibitory activities against all targets as compared to the standard inhibitors, revealed by IC 50 values. The K i values of the new PEPPSI-Pd-NHC complexes 1a-e for hCA I, hCA II, AChE, BChE, and α-Glu were obtained in the ranges of 18.98-32.65, 22.95-38.13, 3.67-11.65, 4.09-9.36, 186.92-287.45 µM, respectively. Among the synthesized complexes, the most potent complexes were 1c toward hCA I and II with K i values 18.98 and 22.95 µM, and 1d toward AChE and BChE with K i  = 3.67 and 4.09 µM, respectively., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

The method for producing 4-trifluoromethoxybenzyl substituted benzimidazolium salts is described in this article. The method is based on the reaction of 4-trifluoromethoxybenzyl substituent alkylating agent with 1-alkylbenzimidazole. This method yielded 1-(4-trifluoromethoxybenzyl)-3-alkylbenzimidazolium bromide salts. These benzimidazolium salts were characterized by using 1 H-NMR, 13 C-NMR, FT-IR spectroscopy, and elemental analysis techniques. The crystal structure of 1f was enlightened by single crystal X-ray diffraction studies. Also, the enzyme inhibition effects of the synthesised compounds were investigated. They demonstrated highly potent inhibition effect on acetylcholinesterase (AChE) and carbonic anhydrases (hCAs) (K i values are in the range of 7.24±0.99 to 39.12±5.66 nM, 5.57±0.96 to 43.07±11.76 nM, and 4.38±0.43 to 18.68±3.60 nM for AChE, hCA I, and hCA II, respectively). In molecular docking study, the interactions of active compounds showing activity against AChE and hCAs enzymes were examined. The most active compound 1f has -10.90 kcal/mol binding energy value against AChE enzyme, and the potential structure compound 1e, which has activity against hCA I and hCA II enzymes, was -7.51 and -8.93 kcal/mol, respectively., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

DNA has become the target of metal complexes in cancer drug discovery. Due to the side effects of widely known cisplatin and its derivative compounds, alternative metal-based drug discovery studies are still ongoing. In this study, the DNA-binding ability of Pd(II) and Pt(II) complexes of four phosphorus Schiff base ligands and four hydrazonoic-phosphines are investigated by using in silico analyses. Phosphorus Schiff base-Pd(II) complexes encoded as B1 and B2 with the best DNA-binding potential are synthesized and characterized. The DNA-binding potentials of these two new Pd(II) complexes are also investigated experimentally, and their antitumor properties are demonstrated in vitro in A549, MCF7, HuH7, and HCT116 cancer cells. The mechanisms of these metal complexes that kill the cells mentioned above in different activities are elucidated by flow cytometry apoptosis analysis and colony formation analysis The in silico binding energies of these two new palladium complexes ΔG ( B1 ): -4.51 and ΔG ( B2 ): -6.04 kcal/mol, and their experimental DNA-binding constants were found as Kb ( B1 ): 4.24 × 10 5 , Kb ( B2 ): 4.98 × 10 5 ). The new complexes, which show different antitumor effects in different cells, are the least effective in HuH7 liver cells, while they showed the best antitumor properties in HCT116 colon cancer cells.

A new cationic indolium based styryl dye (Ci) as a fluorescent probe was synthesized and its anions selectivity/sensitivity properties/molecular interactions with protease enzymes (pepsin/trypsin) and ctDNA has been studied by spectroscopic and computational methods. The fluorescence measurements at different temperatures indicated that quenching mechanism of enzymes by Ci was static. ΔH and ΔS data pointed out electrostatic/hydrophobic interactions with pepsin, and also hydrogen bonds/van der Waals forces with trypsin of Ci. According to Förster's non-radiative energy transfer, binding distances (r) were calculated as 3.53/3.27 nm for pepsin/trypsin. It was also investigated that groove binding is effective in interaction with ctDNA. The results were supported with molecular docking analyzes which have same tendency. Ci has been demonstrated hypsochromic effect with a decrease in polarity of solvents and it showed highly selective colorimetric and fluorometric sensing behavior for cyanide in organic solvent and in aqueous solution. 1 H NMR titration was performed to examine the interaction mechanism between Ci and cyanide. The LOD values of cyanide ion were reported as 4.87 × 10 -9  M and 9.70 × 10 -7  M in DMSO and DMSO/H 2 O binary mixture, respectively. In addition, sensitivity of Ci as a chemosensor to cyanide was investigated in bitter almond samples., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this research, a series of N-phenylsulfonamide derivatives (1-12) were designed, synthesized, and investigated for their inhibitory potencies against carbonic anhydrase isoenzymes I, II, and IX (hCA I, hCA II, and hCA IX) and cholinesterases (ChE), namely, acetylcholinesterase and butyrylcholinesterase. These compounds, whose inhibition potentials were evaluated for the first time, were characterized by spectroscopic techniques ( 1 H- and 13 C-NMR and FT-IR). CA isoenzyme inhibitors are significant therapeutic targets, especially owing to their preventive/activation potential in the therapy processes of some diseases such as cancer, osteoporosis, and glaucoma. On the other hand, Cholinesterase inhibitors are valuable molecules with biological importance that can be employed in the therapy process of Alzheimer's patients. The results showed that the tested molecules had enzyme inhibition activities ranging from 9.7 to 93.7 nM against these five metabolic enzymes. Among the tested molecules, the methoxy and the hydroxyl group-containing compounds 10, 11, and 12 exhibited more enzyme inhibition activities when compared to standard compounds acetazolamide, sulfapyridine, and sulfadiazine for CA isoenzymes and neostigmine for ChE, respectively. Of these three molecules, compound 12, which had a hydroxyl group in the para position in the aromatic ring, was determined to be the most active molecule against all enzymes. In silico work, molecular docking has also shown similar results and is consistent with the experimental data in the study. As a result, we can say that some of the tested molecules might be used as promising inhibitor candidates for further studies on this topic., (© 2022 John Wiley & Sons Ltd.)

This study was designed to screen the phytochemical composition and investigate the biological activities of Hedysarum candidissimum extracts and also support the results with molecular docking studies. LC/MS/MS analysis revealed the presence of 22 phytochemical constituents (mainly phenolic acids, flavonoids, and flavonoid glycosides) in the plant structure. The methanol extract exhibited the strongest antioxidant activity among all the extracts with its strong DPPH radical scavenging and iron reducing capacity, as well as high phenolic and flavonoid contents. Additionally, it was found to be the most promising acetylcholinesterase (AChE: IC 50 : 93.26 μg/mL) and α-glycosidase (AG: IC 50 : 28.57 μg/mL) inhibitory activities, supported by the major phenolics of the species through in silico studies. Ethyl acetate extract had the strongest cytotoxic effect on HT-29 (IC 50 : 63.03 μg/mL) and MDA-MB-453 (IC 50 : 95.36 μg/mL) cancer cell lines. Both extracts exhibited considerable apoptotic and anti-migrative effects on HT-29 cells. The investigations provide phyto-analytical and bio-pharmacological results which can be extended by in vivo studies in the future., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

The aim of this study was to identify and quantify the phenolic composition of Turanecio hypochionaeus Bosse and determine the anti-urease, anti-lipase, antidiabetic, anti-melanogenesis, antibacterial, and anti-Alzheimer properties. IC 50 results for all enzymes were obtained between 0.234-116.50 μg/mL and this plant inhibited HMG_CoA R and glucosidase enzymes more with IC 50 values of 0.234 and 116.50 μg/mL, respectively. Among the 11 secondary metabolites identified in T. hypochionaeus extract, chlorogenic acid 255.459±1.17 μg g -1 ), benzoic acid (56.251±1.98 μg g -1 ), and catechin (29.029±0.27 μg g -1 ) were determined as the most abundant phenolic compounds. According to the results of the tested microorganisms, the plant extracts showed antimicrobial and antifungal properties in a dose-dependent manner. In molecular docking study, the interactions of active compounds extracted from Turanecio hypochionaeus plant and showing activity against diverse metabolic enzymes were examined. The most active compound 1, (chlorogenic acid) has -12.80, -12.80, -12.60 and -12.00 kcal/mol binding energy value against HMG_CoA R, and α-amylase, α-glucosidase, and lipase, respectively., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Variety of 2-aryl quinoxaline derivatives 1-23 were synthesized in good yields, by reacting 1,2-phenylenediamine with varyingly substituted phenacyl bromides in the presence of pyridine catalyst. All molecules 1-23 were characterized by spectroscopic techniques and evaluated for their diverse biological potential against α-amylase (α-AMY), α-glucosidase (α-GLU), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes. Synthetic derivatives possess enhanced inhibitory potential against all enzymes at nanomolar concentrations. In particular, compound 14 was found much superior with IC 50  = 294.35, 198.21, 17.04, and 21.46 nM against α-AMY, α-GLU, AChE, and BChE, respectively, as compared to standard inhibitors. Furthermore, selected potent compounds, including 3, 4, 8, 14, 15, 17, and 18, were subjected to molecular docking studies to decipher the binding energies and interactions of ligands (synthetic molecules) with all four target enzymes., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Pandemic COVID-19 infections have spread throughout the world. There is no effective treatment against this disease. Viral RNA-dependent RNA polymerase (RdRp) catalyzes the replication of RNA from RNA and the main protease (M pro ) has a role in the processing of polyproteins that are translated from the RNA of SARS-CoV-2, and thus these two enzymes are strong candidates for targeting by anti-viral drugs. Small molecules such as lopinavir and favipiravir significantly inhibit the activity of M pro and RdRp in vitro . Studies have shown that structurally modified lopinavir, favipiravir, and other similar compounds can inhibit COVID-19 main protease (M pro ) and RNA-dependent RNA polymerase (RdRp). In this study, lopinavir and its structurally similar compounds were chosen to bind the main protease, and favipiravir was chosen to target RNA-dependent RNA polymerase. Molecular docking and the quantitative structure-activity relationships (QSAR) study revealed that the selected candidates have favorable binding affinity but less druggable properties. To improve the druggability, four structural analogues of lopinavir and one structural analogue of favipiravir was designed by structural modification. Molecular interaction analyses have displayed that lopinavir and favipiravir analogues interact with the active site residues of M pro and RdRp, respectively. Absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, medicinal chemistry profile, and physicochemical features were shown that all structurally modified analogues are less toxic and contain high druggable properties than the selected candidates. Subsequently, 50 ns molecular dynamics simulation of the top four docked complexes demonstrated that CID44271905, a lopinavir analogue, forms the most stable complex with the M pro . Further MMPBSA analyses using the MD trajectories also confirmed the higher binding affinity of CID44271905 towards M pro . In summary, this study demonstrates a new way to identify leads for novel anti-viral drugs against COVID-19. Communicated by Ramaswamy H. Sarma.

Interaction type of modafinil with calf thymus DNA (ct-DNA) was examined systematically using ethidium bromide (EB) as a fluorescence probe by fluorescence spectroscopy, UV-Vis spectroscopy, viscosity and molecular docking method. The fluorescence quenching mechanism of ct-DNA-EB by modafinil can be combination of static and dynamic quenching. Results of UV-Vis absorption, competitive binding with Hoechst 33258, ionic strength effect studies, viscosity measurements were confirmed that the interaction type of modafinil with ct-DNA was intercalation. According to docking studies R-modafinil showed better interaction with ct-DNA which is consistent with known pharmacological properties of modafinil. The calculated thermodynamic parameters, enthalpy and entropy change, suggested that the driven forces are hydrogen bonding or van der Walls forces. Results of the docking studies were compatible with the experimental results and confirmed the hydrogen bond formation between modafinil and ct-DNA., 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 © 2021 Elsevier B.V. All rights reserved.)

Here, we report the synthesis, characterization, and biological activities of a series of benzimidazolium salts bearing the trifluoromethylbenzyl group. All benzimidazolium salts were characterized by using nuclear magnetic resonance (NMR) ( 1 H NMR and  13 C NMR), Fourier transform-infrared spectroscopy, and elemental analysis techniques. The crystal structures of some of these compounds were obtained by the single-crystal X-ray diffraction method. Furthermore, the acetylcholinesterase (AChE) and α-glycosidase (α-Gly) enzyme inhibition activities of these compounds were investigated. The obtained results revealed that 2e, with K i value of 1.36 ± 0.34 µM against AChE and 3d with K i value of 91.37 ± 10.38 µM against α-Gly, were the most potent compounds against both assigned enzymes. It should be noted that most of the synthesized compounds were more potent than standard inhibitor tacrine (TAC) against AChE. In silico studies, we focused on compound 2e, 3d, 3e, and 3f as potent inhibitors of AChE and α-Gly, the compound 2e showed good binding energy (-10.23 kcal/mol), among the three selected compounds and positive control (-10.18, -10.08, and -7.37 kcal/mol for 3d, 3f, and TAC, respectively). Likewise, as a result of the same compounds against the α-Gly enzyme, the compound 3d had the highest binding affinity (-8.39 kcal/mol) between the four selected compounds and the positive control (-8.27, -8.10, -8.06, and -7.53 kcal/mol for 3f, 3e, 2e, and acarbose, respectively). From the absorption, distribution, metabolism, excretion, and toxicity analyses, it can be concluded that the compounds under consideration exhibited more drug-likeness properties in the prediction studies compared to positive controls., (© 2022 Wiley Periodicals LLC.)

A novel infectious agent, SARS-CoV-2, is responsible for causing the severe respiratory disease COVID-19 and death in humans. Spike glycoprotein plays a key role in viral particles entering host cells, mediating receptor recognition and membrane fusion, and are considered useful targets for antiviral vaccine candidates. Therefore, computational techniques can be used to design a safe, antigenic, immunogenic, and stable vaccine against this pathogen. Drawing upon the structure of the S glycoprotein, we are trying to develop a potent multi-epitope subunit vaccine against SARS-CoV-2. The vaccine was designed based on cytotoxic T-lymphocyte and helper T-lymphocyte epitopes with an N-terminal adjuvant via conducting immune filters and an extensive immunoinformatic investigation. The safety and immunogenicity of the designed vaccine were further evaluated via using various physicochemical, allergenic, and antigenic characteristics. Vaccine-target (toll-like receptors: TLR2 and TLR4) interactions, binding affinities, and dynamical stabilities were inspected through molecular docking and molecular dynamic (MD) simulation methods. Moreover, MD simulations for dimeric TLRs/vaccine in the membrane-aqueous environment were performed to understand the differential domain organization of TLRs/vaccine. Further, dynamical behaviors of vaccine/TLR systems were inspected via identifying the key residues (named HUB nodes) that control interaction stability and provide a clear molecular mechanism. The obtained results from molecular docking and MD simulation revealed a strong and stable interaction between vaccine and TLRs. The vaccine's ability to stimulate the immune response was assessed by using computational immune simulation. This predicted a significant level of cytotoxic T cell and helper T cell activation, as well as IgG, interleukin 2, and interferon-gamma production. This study shows that the designed vaccine is structurally and dynamically stable and can trigger an effective immune response against viral infections., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Protein kinases emerged as one of the most successful families of drug targets due to their increased activity and involvement in mediating critical signal transduction pathways in cancer cells. Recent evidence suggests that eukaryotic elongation factor 2 kinase (eEF-2K) is a potential therapeutic target for treating some highly aggressive solid cancers, including lung, pancreatic and triple-negative breast cancers. Thus, several compounds have been developed for the inhibition of the enzyme activity, but they are not sufficiently specific and potent. Besides, the crystal structure of this kinase remains unknown. Hence, the functional organization and regulation of eEF-2K remain poorly characterized. For this purpose, we constructed a homology model of eEF-2K and then used docking methodology to better understanding the binding mechanism of eEF-2K with 58 compounds that have been proposed as existing inhibitors. The results of this analysis were compared with the experimental results and the compounds effective against eEF-2K were determined against eEF-2K as a result of both studies. And finally, molecular dynamics (MD) simulations were performed for the stability of eEF-2K with these compounds. According to these study defined that the binding mechanism of eEF-2K with inhibitors at the molecular level and elucidated the residues of eEF-2K that play an important role in enzyme selectivity and ligand affinity. This information may lead to new selective and potential drug molecules to be for inhibition of eEF-2K.Communicated by Ramaswamy H. Sarma.

Gastric cancer (GC) has limited effective treatment options and is followed up with biomarkers that have insufficient sensitivity and specificity. Recent studies on Collagen Type X Alpha 1 Chain (COL10A1) show that the COL10A1 gene may be a diagnostic and/or prognostic biomarker for different cancer types. Moreover, its relationship with the Sex determining Region Y (SRY)-related High-Mobility Group (HMG) box (SOX9) gene which is also a transcription factor, was discovered recently, and co-expression of these two genes are associated with the development of GC. However, to the best of our knowledge, there is no study in the literature on how potential damaging mutations in the SOX9 and COL10A1 genes can affect their interactions. The aim of this study is to investigate the interactions of wild-type and potentially damaging mutated structures of COL10A1 and SOX9 genes. Thus, outputs for drug development and therapeutic strategies for GC can be obtained. For this purpose, structure validation and energy minimization analyses as well as docking and binding affinity calculations were performed. As a result, it was found that all investigated mutations (P563S, I588L, T624A, H165R and N110T) increased the binding affinity between the COL10A1-SOX9 complex, especially the N110T and H165R mutants in SOX9. As a conclusion, the N110T and H165R mutants in SOX9 may contribute to tumor progression. Therefore, it is important to consider these mutations for future therapeutic strategies.Communicated by Ramaswamy H. Sarma.

N-heterocyclic carbene (NHC) adducts have shown remarkable biological potential for numerous medical applications. With an aim to improve biological potential of benzimidazolium salts, newer analogues of benzimidazole and their silver complexes were synthesized and characterized. Synthesized salts (L 1 -L 2 ) and silver complexes (C 1 -C 2 ) were confirmed through elemental analysis, UV-visible spectroscopy, FTIR, 1 H NMR & 13 C NMR spectroscopy. The compounds C1 & C2 were found stable in solution form for studied time period when examined spectroscopically and showed optimum lipophilicity when measured for their partition coefficient through flask shake method. Synthesized compounds showed good antimicrobial potential against gram positive bacterial strain S. Aureus with IC 50 2.02±0.12 and 2.11±0.13 µM respectively while 2.11±0.1 and 2.28±0.17 µM against gram negative bacterial strain E. Coli for C1 and C2 respectively. The interaction study of the related compounds with DNA was predicted by molecular docking study, which confirmed that the studied compound C1 (-8.04 kcal/mol) has a higher binding energy than compound C2 (-4.23 kcal/mol); Also, the compound C1 exhibits a better affinity against to DNA than Ethidium bromide (-7.68 kcal/mol) and cisplatin (-6.21 kcal/mol).The claim was practically assured through spectroscopic and viscometeric method which confirmed that compounds have good affinity for DNA with binding constant kb, 5.78×10 4 M -1 and 6.84×10 4 M -1 for C1 and C2 respectively., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The levels of reactive oxygen species (ROS) are tightly controlled and regulated by Nuclear Factor Erythroid-2-Like 2 (Nrf2) transcription factor, which is the main regulator of antioxidant responses and its suppressor protein Kelch-like ECH-associated protein 1 (Keap1). Our previous study has identified six novel changes in Nrf2/Keap1 pathway in pediatric ALL, which were described for the first time. These changes in the pathway are likely to alter the evolutionary process of amino acids and cause structural changes in the final products of genes. In this study, we aimed to compare the pathogenicity of eight determined mutations reported in our previous study by utilizing different programs with different algorithms and molecular dynamics simulation. Since it is too difficult to handle each existing mutation in a wet laboratory, in silico methods may give suggestion to choose the important mutations for further analysis and to establish the appropriate patient population and conduct wet laboratory studies. For this purpose, four different algorithms were used to evaluate the effects of single amino acid mutation. In addition, root-mean-square deviation, root-mean-square fluctuation and free-energy landscape analyses were performed to observe stability, flexibility and energetically favorable conformations, respectively, for each amino acid mutation. As a result, our study emphasizes the importance of Keap1 mutations in pediatric ALL Nrf2/Keap1 pathway, a total of eight mutations, two of which were shown for the first time in our study. Especially the mutations in the Keap1 Broad-Complex, Tramtrack and Bric-à-brac domain are worthy of attention.Communicated by Ramaswamy H. Sarma.

SARS-CoV-2 is a new generation of coronavirus, which was first determined in Wuhan, China, in December 2019. So far, however, there no effective treatment has been found to stop this new generation of coronavirus but discovering of the crystal structure of SARS-CoV-2 main protease (SARS-CoV-2 Mpro) may facilitate searching for new therapies for SARS-COV-2. The aim was to assess the effectiveness of available FDA approved drugs which can construct a covalent bond with Cys145 inside binding site SARS-CoV-2 main protease by using covalent docking screening. We conducted the covdock module MMGBSA module in the Schrodinger suite 2020-1, to examine the covalent bonding utilizing. Besides, we submitted the top three drugs to molecular dynamics simulations via Gromacs 2018.1. The covalent docking showed that saquinavir, ritonavir, remdesivir, delavirdine, cefuroxime axetil, oseltamivir and prevacid have the highest binding energies MMGBSA of -72.17, -72.02, -65.19, -57.65, -54.25, -51.8, and -51.14 kcal/mol, respectively. The 50 ns molecular dynamics simulation was conducted for saquinavir, ritonavir and remdesivir to evaluate the stability of these drugs inside the binding pocket of SARS-CoV-2 main protease. The current study provides a powerful in silico results, means for rapid screening of drugs as anti-protease medications and recommend that the above-mentioned drugs can be used in the treatment of SARS-CoV-2 in combined or sole therapy.Communicated by Ramaswamy H. Sarma.

Cell-division protein kinases (CDKs) are gorgeous examples of targets for the helpful treatment of cancer by using multi-target inhibitors. Specifically, targeting cell-division protein kinase1/cyclin B (CDK1/Cyclin B), cell-division protein kinase 2/cyclin A (CDK2/Cyclin A) and cell-division protein kinase 4/cyclin D1 (CDK4/Cyclin D1) are considered a safe strategy to over the toxicity complications which are emerging from low specificity. In this work, we conducted the double docking and molecular dynamics to explicate the effect of amygdalin upon conformational modifications of selected targets. Moreover, the principal component analysis (PCA) was employed to inspect the effect of amygdalin on the fundamental motions of the each protein as target. Docking results illustrated that the binding free energies of amygdalin (AMY) to CDK1/Cyclin B, CDK 2/Cyclin A and CDK 4/Cyclin D1 were to be -9.41, -9.02 and -10.6 kcal/mol, respectively. The PCA results disclosed that binding of the AMY minimized the fundamental dynamics of CDK1/Cyclin B and CDK2/Cyclin A. The obtained results can give an insight into inhibitory activity of amygdalin that could help in designing of potential inhibitors. In the other word, it can be used AMY to inhibit other mechanisms and/or hallmarks of cancer.Communicated by Ramaswamy H. Sarma.

Eukaryotic elongation factor 2 kinase (eEF-2K) is an unusual alpha kinase involved in protein synthesis through phosphorylation of elongation factor 2 (EF2). eEF-2K is highly overexpressed in breast cancer, and its activity is associated with significantly shortened patient survival and proven to be a potential molecular target in breast cancer. The crystal structure of eEF-2K remains unknown, and there is no potent, safe, and effective inhibitor available for clinical applications. We designed and synthesized several generations of potential inhibitors. The effect of the inhibitors at the binding pocket of eEF-2K was analyzed after developing a 3D target model by using a domain of another α-kinase called myosin heavy-chain kinase A (MHCKA) that closely resembles eEF-2K. In silico studies showed that compounds with a coumarin-chalcone core have high predicted binding affinities for eEF-2K. Using in vitro studies in highly aggressive and invasive (MDA-MB-436, MDA-MB-231, and BT20) and noninvazive (MCF-7) breast cancer cells, we identified a lead compound that was highly effective in inhibiting eEF-2K activity at submicromolar concentrations and at inhibiting cell proliferation by induction of apoptosis with no toxicity in normal breast epithelial cells. In vivo systemic administration of the lead compound encapsulated in single lipid-based liposomal nanoparticles twice a week significantly suppressed growth of MDA-MB-231 tumors in orthotopic breast cancer models in nude mice with no observed toxicity. In conclusion, our study provides a highly potent and in vivo effective novel small-molecule eEF-2K inhibitor that may be used as a molecularly targeted therapy breast cancer or other eEF-2K-dependent tumors., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

This study focused on synthesis various dimethyl N-benzyl-1H-1,2,3-triazole-4,5-dicarboxylate and (N-benzyl-1H-1,2,3-triazole-4,5-diyl)dimethanol derivatives under the conditions of green chemistry without the use of solvent and catalysts. Their inhibition properties were also investigated on xanthine oxidase (XO) activity. All dimethanol and dicarboxylate derivatives exhibited significant inhibition activities with IC 50 values ranging from 0.71 to 2.25 μM. Especially, (1-(3-bromobenzyl)-1H-1,2,3-triazole-4,5-diyl)dimethanol (5c) and dimethyl 1-(4-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylate (6 g) compounds were found to be the most promising derivatives on the XO enzyme inhibition with IC 50 values 0.71 and 0.73 μM, respectively. Moreover, the double docking procedure was to evaluate compound modes of inhibition and their interactions with the protein (XO) at atomic level. Surprisingly, the docking results showed a good correlation with IC 50 [correlation coefficient (R 2  = 0.7455)]. Also, the docking results exhibited that the 5c, 6f and 6 g have lowest docking scores -4.790, -4.755, and -4.730, respectively. These data were in agreement with the IC 50 values. These results give promising beginning stages to assist in the improvement of novel and powerful inhibitor against XO., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Amygdalin possesses anticancer properties and induces apoptosis. Based on experimental studies the presence of amygdalin with cancer cells led to activate the caspase-3 and BAX and inhibits Bcl-2 and Poly (ADP-ribose) polymerase-1 (PARP-1) but without deep information on action mode of these activities. Herein, we leaped forward to examine the molecular dynamics of the bound amygdalin and free ligand proteins, to identify precise action (conformation changes in targeted proteins) of amygdalin through using double docking and molecular dynamics (MD) simulations for 50 ns time scale. The MD simulations revealed that the binding of amygdalin led to disrupting the interaction between the Bcl-2/BAX complex. We furthermore conducted MD simulation for Bcl-2/amygdalin to investigate the stability of the complex which is responsible for inhibition of Bcl-2. It has been obtained a stable Bcl-2/amygdalin complex during the 50 ns. The results give a detail explanation of how amygdalin activates BAX and inhibits Bcl-2. For caspase-3, the matter is different, we found that amygdalin led to disrupting the interaction of caspase-3's two chains for intervals during 50 ns and then bind together repeatedly. The mechanism of caspase-3's activation through switching by disrupt the interacts for periodic intervals manner. For PARP-1, the dynamics simulations results indicated amygdalin interacts with PARP-1's binding site and forms stable interaction during simulation to render it inactive. Hence, amygdalin revealed a supernatural behavior through the MD simulations: it revealed a further clarification of the mystery amygdalin's experimental action which can act as a multifunctional drug in the cancer therapeutics.Communicated by Ramaswamy H. Sarma.

Background and Objective: Historically, amygdalin has been used as alternative medicine or in vitro and in vivo studies, but no single study exists which discusses the structural mechanism of amygdalin at a molecular level. This paper inquiries into the inhibitory actions of amygdalin on the selected targets: AKT1, FAK, and ILK, which are regulators for various mediated signaling pathways, and are associated with cell adhesion, migration, and differentiation. In order to get details at the molecular level of amygdalin's inhibitory activities against chosen proteins, molecular modeling and simulation techniques including double docking, molecular dynamics simulation, free energy landscape analysis, and binding free energy calculation were exerted., Methods: To get molecular level details of amygdalin inhibitory effects against the relevant proteins; here the utilized tools are the following: the double docking, molecular dynamics simulation, free energy landscape analysis, g_mmpbsa, and interaction entropy were used to evaluate the inhibitory activity against targeted proteins., Results: The computational calculations revealed that amygdalin inhibits the selected targets via block the ATP-binding pocket of AKT1, FAK, and ILK by forming stable hydrogen bonds. Moreover, free energy landscape, FEL exposed that amygdalin stabilized the global conformations of both FAK and ILK proteins to the minimum global energy besides it reduced the essential dynamics of FAK and ILK proteins. MMPBSA computations provided further evidence for amygdalin's stability inside the ATP-binding pocket of AKT1, FAK, and ILK with a binding free energy of 45.067, -13.033, 13.109 kJ/mol, respectively. The binding free energies are lastly consistent with the hydrogen bonding and pairs within 0.35 nm results. The decomposition of binding energy shows the pivotal amino acid residues responsible for the stability of amygdalin's interactions inside the ATP-binding sites by forming hydrogen bonds., Conclusions: Before this work, it was enigmatic to make predictions about how amygdalin inhibits metastasis of cancer. But the computational results contribute in several ways to our understanding of amygdalin activity and provide a basic insight into the activity of amygdalin as a multi-target drug in the metastasis and invasion of cancer., Competing Interests: Declaration of Competing for Interest The authors declared that they have no conflicts of interest in this work., (Copyright © 2020. Published by Elsevier B.V.)

In this study, an electrochemical DNA biosensor was developed using a straightforward methodology to investigate the interaction of indinavir with calf thymus double-stranded deoxyribonucleic acid (ct-dsDNA) for the first time. The decrease in the oxidation signals of deoxyguanosine (dGuo) and deoxyadenosine (dAdo), measured by differential pulse voltammetry, upon incubation with different concentrations of indinavir can be attributed to the binding mode of indinavir to ct-dsDNA. The currents of the dGuo and dAdo peaks decreased linearly with the concentration of indinavir in the range of 1.0-10.0 μg/mL. The limit of detection and limit of quantification for indinavir were 0.29 and 0.98 μg/mL, respectively, based on the dGuo signal, and 0.23 and 0.78 μg/mL, respectively, based on the dAdo signal. To gain further insights into the interaction mechanism between indinavir and ct-dsDNA, spectroscopic measurements and molecular docking simulations were performed. The binding constant (K b ) between indinavir and ct-dsDNA was calculated to be 1.64 × 10 8  M -1 , based on spectrofluorometric measurements. The obtained results can offer insights into the inhibitory activity of indinavir, which could help to broaden its applications. That is, indinavir can be used to inhibit other mechanisms and/or hallmarks of viral diseases., Competing Interests: The authors declare that there are no conflicts of interest., (© 2020 Xi'an Jiaotong University. Production and hosting by Elsevier B.V.)

In this paper, we report a fluorescent sensor array approach for the urinary detection of a prohibited substance in sports, meldonium. Four chemosensors with ethidium bromide scaffolds were employed in this method. The interaction between meldonium and chemosensors was investigated by different techniques, such as ultraviolet-visible absorption and fluorescence spectroscopy, nuclear magnetic resonance, and mass spectrometry. Molecular dynamics simulation was also used to elucidate and support the interaction mechanisms between meldonium and the chemosensors. Differential responses obtained from the sensor array enabled the qualitative and quantitative analyses of meldonium with low error values. This method was able to detect and quantify meldonium at the nM level, fulfilling the requirements of minimum performance defined by the World Anti-Doping Agency.

Rho-associated protein kinases (ROCKs) are a member of the serine/threonine protein kinase family and potential therapeutic target for various diseases. This enzyme has two isoforms, Rho-associated protein kinase I (ROCKI) and Rho-associated protein kinase II (ROCKII). They share an overall 65% homology in all amino acid sequence and 92% homology in kinase domains. Since, the kinase domains of ROCKI and ROCKII are highly conserved and similar, the discovery and design of isoform-selective inhibitors are more challenging. Thus, most currently available agents that is against ROCKs exhibit low selectivity and severe side effects. Therefore, this study aimed to elucidate the interaction of compounds that indicated high potential in experimental studies against ROCKI and ROCKII enzymes in the molecular level with molecular modeling techniques. Firstly, we determined the interaction property of catalytic sites of the ROCKs by analyzing with molecular docking. Based on these results, the best ligands (50 compounds) corresponding to experimental studies were selected, and then absorption, distribution, metabolism and excretion - toxicity (ADMET) analysis of these compounds were implemented. According to these study results, the compound 40 for ROCKI and the compound 50 for ROCKII were identified as selective and highly potent inhibitors. And finally, molecular dynamics (MD) simulations were performed for the stability of ROCKs with identified compounds. In the light of this study, it will be possible to treat diseases that ROCKs have a role by developing more effective and specific ROCK inhibitors. Communicated by Ramaswamy H. Sarma.

This study presents evaluation of the possible interaction mechanism between calf thymus dsDNA and three calcium antagonists; nifedipine, lercanidipine and amlodipine. The interactions between Nifedipine-dsDNA and Lercanidipine-dsDNA were investigated by differential pulse voltammetry using two different interaction methods; at the dsDNA-electrochemical biosensor surface and in bulk incubated solution. Amlodipine was used as model drug in bulk incubated solution. The decrease in the peak current of guanine and adenine were used as an indicator for confirmation of the interaction event in acetate buffer of pH 4.70. In bulk incubated solution, after interaction with Nifedipine and Amlodipine the guanine signal was almost disappeared. At the dsDNA modified glassy carbon electrode surface, the peak currents of guanine and adenine were decreased while Nifedipine and Lercanidipine interacts with DNA. The interactions between Nifedipine-dsDNA and Lercanidipine-dsDNA were further studied by UV-Vis absorption spectroscopy which indicates the intermolecular interaction between these drugs and ds-DNA can be mainly through hydrogen bonding and van der Waals forces. Molecular docking calculations shown that the AMP-1-2, NDP and LDP-1-2-ctDNA having groove binding. Beside spectral data, docking studies elicited that AMP-1-2, NDP and LDP-1-2 complexes have different interaction and conformation trends to target (ctDNA)., (Copyright © 2019. Published by Elsevier B.V.)

Mode of interaction of a new tetrahydrocarbazole derivative with ct-DNA has been investigated systematically using fluorescence spectroscopy, UV-Vis spectroscopy and circular dichroism spectroscopy. It is concluded that TAH could intercalate into the base pairs of ct-DNA, and the fluorescence quenching by ct-DNA was static quenching type. Beside the multispectroscopic results, computational studies were done. Molecular docking results revealed that the TAH-DNAs complexes might be classified as druggable molecule in drug design. Additionally, DNA binding studies exhibited that TAH complexes have different interaction and orientation abilities to each DNA isomer. Combination of experimental and computational data showed that reported TAH is promising structure and deserves further applications.

The interaction mechanisms of two ethidium derivatives, 3,8-dibenzoylamino-5-ethyl-6-phenylphenantridinium chloride (E2) and 3,8-diphenylacetylamino-5-ethyl-6-phenylphenantridinium chloride (E3) with serum albumins (BSA and HSA) have been investigated by a combined experimental and computational approach. Fluorescence quenching and UV-vis results revealed that the interaction of derivatives with albumins resulted in formation of ground-state complexes and the obtained Stern-Volmer quenching constants designate the presence of a static component in the quenching mechanisms. Thermodynamic parameters (ΔH and ΔS values) point out the ionic interactions play the major role in E2-BSA, E2-HSA and E3-HSA complexes. The van der Waals interactions are dominant forces in E3-BSA complex. Moreover, the obtained results in this study were supported with computational analyzes which have same tendency.