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Three new cycloartane triterpenoids, commikuanoids A-C (1-3), together with four known compounds 4-7, were isolated from the resin of Commiphora kua. Their structures were confirmed by advanced NMR techniques such as 1D ( 1 H and 13 C) and 2D (HMBC, HSQC, COSY, NOESY and NOE) and high-resolution mass spectrometry (HRMS). Five compounds (1-5) were screened for in vitro carbonic anhydrase II (CA II) inhibitory activity. All the tested compounds demonstrated significant activity against CA II with IC 50 values ranging from 4.9-19.6 μM. Moreover, the binding pattern of each compound in the binding site of CA-II was predicted through in silico molecular docking approach. It was observed that compounds 2, 4, and 5 binds with the Zn ion present in the active site of CA II, while compounds 1 and 3 mediated hydrogen bonding with Thr199 of CA-II, and all the compounds showed good binding score (> - 5 kcal/mol)., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This study aimed to investigate the synthesis and potential vasodilator effect of a novel ruthenium complex, cis-[Ru(bpy) 2 (2-MIM)(NO 2 )]PF 6 (bpy = 2,2'-bipyridine and 2-MIM = 2-methylimidazole) (FOR711A), containing an imidazole derivative via an in silico molecular docking model using β1 H-NOX (Heme-nitric oxide/oxygen binding) domain proteins of reduced and oxidized soluble guanylate cyclase (sGC). In addition, pharmacokinetic properties in the human organism were predicted through computational simulations and the potential for acute irritation of FOR711A was also investigated in vitro using the hen's egg chorioallantoic membrane (HET-CAM). FOR711A interacted with sites of the β1 H-NOX domain of reduced and oxidized sGC, demonstrating shorter bond distances to several residues and negative values of total energy. The predictive study revealed molar refractivity (RM): 127.65; Log Po/w = 1.29; topological polar surface area (TPSA): 86.26 Å 2 ; molar mass (MM) = 541.55 g/mol; low solubility, high unsaturation index, high gastrointestinal absorption; toxicity class 4; failure to cross the blood-brain barrier and to react with cytochrome P450 (CYP) enzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. After the HET-CAM assay, the FOR711A complex was classified as non-irritant (N.I.) and its vasodilator effect was confirmed through greater evidence of blood vessels after the administration and ending of the observation period of 5 min. These results suggest that FOR711A presented a potential stimulator/activator effect of sGC via NO/sGC/cGMP. However, results indicate it needs a vehicle for oral administration., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A series of heteroleptic Ag(I) complexes bearing 4,6-dimethyl-2-pyrimidinethiol (dmp2SH), i.e., [AgCl(dmp2SH)(PPh 3 ) 2 ] (1), [Ag(dmp2SH)(PPh 3 ) 2 ]NO 3 (2), [Ag(dmp2SΗ)(xantphos)]NO 3 (3), [Ag(μ-dmp2S)(PPh 3 )] 2 (4), [Ag(dmp2S)(xantphos)] (5), [Ag(μ-dmp2S)(DPEphos)] 2 (6) (xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and DPEPhos = bis[(2-diphenylphosphino)phenyl]ether) were synthesized. The complexes display systematic variation of particular structural characteristics which were proved to have a significant impact on their in vitro cytotoxicity and antimicrobial properties. A moderate-to-high potential for bacteria growth inhibition was observed for all complexes, with 2, 3 and 5 being particularly effective against Gram-(+) bacteria (IC 50  = 1.6-4.5 μM). The three complexes exhibit high in vitro cytotoxicity against HeLa and MCF-7 cancer cells (IC 50  = 0.32-3.00 μΜ), suggesting the importance of coordination unsaturation and cationic charge for effective bioactivity. A very low cytotoxicity against HDFa normal cells was observed, revealing a high degree of selectivity (selectivity index ~10) and, hence, biocompatibility. Fluorescence microscopy using 2 showed effective targeting on the membrane of the HeLa cancer cells, subsequently inducing cell death. Binding of the complexes to serum albumin proteins is reasonably strong for potential uptake and subsequent release to target sites. A moderate in vitro antioxidant capacity for free radicals scavenging was observed and a low potential to destroy the double-strand structure of calf-thymus DNA by intercalation, suggesting likely implication of these properties in the bioactivity mechanisms of these complexes. Further insight into possible mechanisms of bioactivity was obtained by molecular modeling calculations, by exploring their ability to act as potential inhibitors of DNA-gyrase, human estrogen receptor alpha, human cyclin-dependent kinase 6, and human papillomavirus E6 oncoprotein., (Copyright © 2021. Published by Elsevier Inc.)

Investigating the drug-AChE binding mechanism is vital in understanding its cogent use in medical practice against Alzheimer's disease (AD). The production and accumulation of oligomers of β-amyloid is a central event in the neuropathology of AD. Beside the inhibition of assembly process, modulation of the aggregation process of these proteins towards minimally toxic pathways may be a possible therapeutic strategy for AD. Hence, the present study aims to examine the effect of multifunctional fused tricyclic 7-hydroxy 4-methyl coumarin analogs (HMC 1 - 5 ) on the self-induced aggregation of β-amyloid using Thioflavin T (ThT) assay, scanning electron microscopic study, AlamarBlue and immune blotting assays and also the binding mechanism with AChE by fluorescence emission, conformational, molecular docking and molecular dynamic simulation studies under physiological pH 7.4. The ThT assay, FE-SEM study, cell line and western blots establish that the HMC 1 - 5 molecules could irreversibly disrupt preformed Aβ 42 fibrils, accelerate the aggregates into micro size co-assembled structures, and effectively eliminate the cytotoxicity of Aβ 1 - 42 . Fluorescence emission studies indicating a strong binding affinity between HMC 1 - 5 and AChE with the binding constants of 1.04 × 10 5 , 3.57 × 10 4 , 1.97 × 10 4 , 3.07 × 10 4 and 2.95 × 10 4 M -1 , respectively and binding sites number found to be 1. CD studies disclosed a partial unfolding in the secondary structure of AChE upon binding with HMC 1 - 5 . Docking analysis inferred that the HMC 1 - 5 were bound through hydrophobic and hydrophilic interactions to the AChE active site. Molecular dynamics simulations emphasized the stability of AChE-HMC 1 - 5 complexes throughout the 100 ns simulations, and the local conformational changes of the residues of AChE validate the stability of complexes. These results provide new and unique complementary approach for modulating the biological effects of the Aβ aggregates by coumarin analogs and new insights for further in vivo investigations as novel anti AD agents., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study reports a novel BglA9 gene of 1345 bp encoding β-glucosidase from Anoxybacillus ayderensis A9, which was amplified and expressed in E. coli BL21 (DE3): pLysS cells, purified with Ni-NTA column having molecular weight of 52.6 kDa and was used in the bioconversion of polydatin to resveratrol. The kinetic parameters values using pNPG as substrate were K m (0.28 mM), V max (43.8 μmol/min/mg), k cat (38.43 s -1 ) and k cat /K m (135.5 s -1  mM -1 ). The BglA9 was active in a broad pH range and had an activity half-life around 24 h at 50 °C. The de-glycosylation efficiency of BglA9 for polydatin was determined by estimating the amount of glucose released after enzymatic reaction by a dinitrosalicylic acid (DNS) assay. The kinetic parameters of BglA9 for polydatin were 5.5 mM, 20.84 μmol/min/mg, 18.28 s -1 and 3.27 s -1  mM -1 for K m , V max , k cat , and k cat /K m values, respectively. The K i value for glucose was determined to be 1.7 M. The residues Gln19, His120, Glu355, Glu409, Glu178, Asn222 may play a crucial role in the deglycosylation as revealed by the 3D structure of enzyme docked with polydatin., (Copyright © 2021. Published by Elsevier B.V.)

Six novel copper(II) complexes with the non-steroidal anti-inflammatory drugs ibuprofen, loxoprofen, fenoprofen and clonixin as ligands were synthesized and characterized by diverse techniques including single-crystal X-ray crystallography. The in vitro scavenging activity of the complexes against 1,1-diphenyl-picrylhydrazyl and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) free radicals and the ability to reduce H 2 O 2 were studied in the context of the antioxidant activity studies. The complexes may interact with calf-thymus DNA via intercalation as revealed by the techniques employed. The affinity of the complexes for bovine and human serum albumins was evaluated by fluorescence emission spectroscopy and the corresponding binding constants were determined. Molecular docking simulations on the crystal structure of calf-thymus DNA, human and bovine serum albumins were also employed in order to study in silico the ability of the studied compounds to bind to these target biomacromolecules, in terms of impairment of DNA and transportation through serum albumins, to explain the observed in vitro activity and to establish a possible mechanism of action., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Fic (filamentation induced by cAMP) proteins regulate diverse cell signaling events by post-translationally modifying their protein targets, predominantly by the addition of an AMP (adenosine monophosphate). This modification is called Fic-mediated adenylylation or AMPylation. We previously reported that the human Fic protein, HYPE/FicD, is a novel regulator of the unfolded protein response (UPR) that maintains homeostasis in the endoplasmic reticulum (ER) in response to stress from misfolded proteins. Specifically, HYPE regulates UPR by adenylylating the ER chaperone, BiP/GRP78, which serves as a sentinel for UPR activation. Maintaining ER homeostasis is critical for determining cell fate, thus highlighting the importance of the HYPE-BiP interaction. Here, we study the kinetic and structural parameters that determine the HYPE-BiP interaction. By measuring the binding and kinetic efficiencies of HYPE in its activated (Adenylylation-competent) and wild type (de-AMPylation-competent) forms for BiP in its wild type and ATP-bound conformations, we determine that HYPE displays a nearly identical preference for the wild type and ATP-bound forms of BiP in vitro and preferentially de-AMPylates the wild type form of adenylylated BiP. We also show that AMPylation at BiP's Thr366 versus Thr518 sites differentially affect its ATPase activity, and that HYPE does not adenylylate UPR accessory proteins like J-protein ERdJ6. Using molecular docking models, we explain how HYPE is able to adenylylate Thr366 and Thr518 sites in vitro. While a physiological role for AMPylation at both the Thr366 and Thr518 sites has been reported, our molecular docking model supports Thr518 as the structurally preferred modification site. This is the first such analysis of the HYPE-BiP interaction and offers critical insights into substrate specificity and target recognition., (© 2021. Cell Stress Society International.)

Gut bacterial β-glucuronidase (GUS) plays a pivotal role in the metabolism and reactivation of a vast of glucuronide conjugates of both endogenous and xenobiotic compounds in the gastrointestinal tract of human, which has been implicated in certain drug-induced gastrointestinal tract (GI) toxicity in clinic. Inhibitors of gut microbial GUS exhibited great potentials in relieving the drug-induced GI toxicity. In this study, Selaginella tamariscina and its major biflavonoid amentoflavone (AMF) were evaluated for their inhibitory activity against Escherichia coli GUS. Two selective probe substrates for GUS (a specific fluorescent probe substrate for GUS, DDAOG and a classical drug substrate for GUS, SN38G) were used in parallel for charactering the inhibition behaviors. Both the extract of S. tamariscina and its major biflavonoid AMF displayed evident inhibitory effects on GUS, and the IC 50 values of AMF against GUS mediated DDAOG and SN-38G hydrolysis were 0.62 and 0.49 μM, respectively. Inhibition kinetics studies indicated that AMF showed mixed type inhibition for GUS-mediated DDAOG hydrolysis, while displayed competitive type inhibition against GUS-mediated SN-38G hydrolysis, with the K i values of 0.24 and 1.25 μM, respectively. Molecular docking studies and molecular dynamics stimulation results clarified the role of amino acid residues Leu361, Ile363, and Glu413 in the inhibition of AMF on GUS. These results provided some foundations for the potential clinical utility of S. tamariscina and its major biflavonoid AMF for treating drug-induced enteropathy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: Mineralization of crystalline particles and the formation of renal calculi contribute to the pathogenesis of crystal nephropathies. Several recent studies on the biology of crystal handling implicated intrarenal crystal deposition-induced necroinflammation in their pathogenesis. We hypothesized that 6,7-dihydroxycoumarin (DHC) inhibit intrarenal crystal cytotoxicity and necroinflammation, and ameliorate crystal-induced chronic kidney disease (CKD)., Main Methods: An unbiased high content screening coupled with fluorescence microscopy was used to identify compounds that inhibit CaOx crystal cytotoxicity. The ligand-protein interactions were identified using computational models e.g. molecular docking and molecular dynamics simulations. Furthermore, mice and rat models of oxalate-induced CKD were used for in-vivo studies. Renal injury, crystal deposition, and fibrosis were assessed by histology analysis. Western blots were used to quantify the protein expression. Data were expressed as boxplots and analyzed using one way ANOVA., Key Findings: An unbiased high-content screening in-vitro identified 6,7-DHC as a promising candidate. Further, 6,7-DHC protected human and mouse cells from calcium oxalate (CaOx) crystal-induced necroptosis in-vitro as well as mice and rats from oxalate-induced CKD in either preventive or therapeutic manner. Computational modeling demonstrated that 6,7-DHC interact with MLKL, the key protein in the necroptosis machinery, and inhibit its phosphorylation by ATP, which was evident in both in-vitro and in-vivo analyses., Significance: Together, our results indicate that 6,7-DHC possesses a novel pharmacological property as a MLKL inhibitor and could serve as a lead molecule for further development of coumarin-based novel MLKL inhibitors. Furthermore, our data identify 6,7-DHC as a novel therapeutic strategy to combat crystal nephropathies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

SARS-CoV-2 is the etiological agent responsible for the ongoing pandemic of coronavirus disease 2019 (COVID-19). The main protease of SARS-CoV-2, 3CLpro, is an attractive target for antiviral inhibitors due to its indispensable role in viral replication and gene expression of viral proteins. The search of compounds that can effectively inhibit the crucial activity of 3CLpro, which results to interference of the virus life cycle, is now widely pursued. Here, we report that epigallocatechin-3-gallate (EGCG), an active ingredient of Chinese herbal medicine (CHM), is a potent inhibitor of 3CLpro with half-maximum inhibitory concentration (IC50) of 0.874 ± 0.005 μM. In the study, we retrospectively analyzed the clinical data of 123 cases of COVID-19 patients, and found three effective Traditional Chinese Medicines (TCM) prescriptions. Multiple strategies were performed to screen potent inhibitors of SARS-CoV-2 3CLpro from the active ingredients of TCMs, including network pharmacology, molecular docking, surface plasmon resonance (SPR) binding assay and fluorescence resonance energy transfer (FRET)-based inhibition assay. The SPR assay showed good interaction between EGCG and 3CLpro with KD ~6.17 μM, suggesting a relatively high affinity of EGCG with SARS-CoV-2 3CLpro. Our results provide critical insights into the mechanism of action of EGCG as a potential therapeutic agent against COVID-19., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

Although the proteins in bromodomain and extra-terminal domain (BET) family are promising therapy drug targets for numerous human diseases, the binding effectiveness is interfered by the competition from non-BET protein BRD9. In this study, molecular docking, molecular dynamics simulations, binding free energy calculations and per-residue energy decomposition methods were employed to clarify the selective inhibition mechanism of nitroxoline. The results showed that the different cavity volume of effective embedding inhibitor and the changes in conserved residues were associated with the significant higher selectivity of inhibitor nitroxoline for BET family than non-BET protein (BRD9). In addition, the non-polar interactions occurred in Phe83, Val87 at ZA loop, and the polar interaction appeared in Met132, Asn135 at BC loop. Therefore, when designing a new inhibitor, it could better improve the inhibitor activity by introducing the heteroatom conjugated pyridine-like moiety and the strong electron-withdrawing nitro-like moiety. Overall, this study not only clarified the molecular mechanism of the selective inhibition of nitroxoline, but also provided insight into designing more effective BET inhibitors in next step., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Scopoletin is a natural anticarcinogenic and antiviral coumarin component. Many studies have proved its anti-cancer effect, and after the preliminary screening of this study, Scopoletin had the best inhibitory effect on Non-small cell lung cancer (NSCLC). But its mechanism for treating NSCLC is still unclear. Therefore, network pharmacology and molecular docking technology were used to explore the potential anti-NSCLC targets and pathways of Scopoletin. The results were verified in vitro., Main Methods: First, Scopoletin was isolated from Fennel and screened to conduct cell proliferation assay on Human lung cancer cell line A549, Human colon cancer cell line HCT-116 and Human hepatoma cell line HepG2 respectively, through the MTT test. Then, the key targets and related pathways were screened through Protein-protein Interaction (PPI) network and "component-target-pathway" (C-TP) network constructed by network pharmacology. And the key targets were selected to dock with Scopoletin via molecular docking. A549 and Human normal lung epithelial cell BEAS-2B were used to verify the results, finally., Key Findings: Through MTT, A549 was chosen as the test cancer cell. From network pharmacology, 16 targets, 27 signaling pathways and 16 GO items were obtained (P < 0.05). The results of PPI network and molecular docking showed that EGFR, BRAF and AKT1 were the key targets of Scopoletin against NSCLC, which were consistent with the western-blot results., Significance: Through network pharmacology, molecular docking and experiments in vitro, Scopoletin was verified to against NSCLC through RAS-RAF-MEK-ERK pathway and PI3K/AKT pathway., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Plakophilin 1 (PKP1), a member of the armadillo repeat family of proteins, is a scaffold component of desmosomes, which are key structural components for cell-cell adhesion. However, PKP1 can be also found in the nucleus of several cells. NUPR1 is an intrinsically disordered protein (IDP) that localizes throughout the whole cell, and intervenes in the development and progression of several cancers. In this work, we studied the binding between PKP1 and NUPR1 by using several in vitro biophysical techniques and in cellulo approaches. The interaction occurred with an affinity in the low micromolar range (~10 μM), and involved the participation of at least one of the tryptophan residues of PKP1 (as shown by fluorescence and molecular docking). The binding region of NUPR1, mapped by NMR and molecular modelling, was a polypeptide patch at the 30s region of its sequence. The association between PKP1 and NUPR1 also occurred in cellulo and was localized in the nucleus, as tested by protein ligation assays (PLAs). We hypothesize that NUPR1 plays an active role in carcinogenesis modulating the function of PKP1., Competing Interests: Declaration of competing interest The authors declare no conflict of interest in regard to this manuscript., (Copyright © 2020. Published by Elsevier B.V.)

In this study, we report the synthesis of eight novel indole-thiazole and indole-thiazolidinone derivatives, as well as their ability to interact with DNA, analysed through the UV-vis absorption, fluorescence, circular dichroism (CD), viscosity techniques and molecular docking. The ctDNA interaction analysis demonstrated different spectroscopic effects and the affinity constants (Kb) calculated by the UV-vis absorption method were between 2.08 × 10 5 and 6.99 × 10 6  M -1 , whereas in the fluorescence suppression constants (Ksv) ranged between 0.38 and 0.77 × 10 4  M -1 and 0.60-7.59 × 10 4  M -1 using Ethidium Bromide (EB) and 4',6-Diamidino-2-phenylindole (DAPI) as fluorescent probes, respectively. Most derivatives did not alter significantly the secondary structure of the ctDNA according to the CD results. None of the compounds was able to change the relative viscosity of the ctDNA. These results prove that compounds interact with ctDNA via groove binding, which was confirmed by A-T rich oligonucleotide sequence assay with compound JF-252, suggesting the importance of both the phenyl ring coupled to C-4 thiazole ring and the bromo-unsubstituted indole nucleus., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This article deals with the synthesis of Schiff-based bis-azomethine-based ligands derived from pyridoxal and aliphatic dihydrazides and the synthesis of nickel(II) complexes C1-C4. The synthesized complexes had their structures elucidated by monocrystal X-ray diffraction and were characterized by vibrational and absorption spectroscopy. The synthesized ligands have characteristics that allow the formation of self-assembly processes, thus, the flexibility or rigidity of the coordination of organic molecules added to the orbitals of the Ni II cation leads to the formation of helical complexes with double helix and a dinucler nickel(II) complex. Moreover, compounds was their interactions with CT-DNA and HSA absorption and emission analysis and molecular docking calculations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The recognition of ACE2 by the receptor-binding domain (RBD) of spike protein mediates host cell entry. The objective of the work is to identify SARS-CoV2 spike variants that emerged during the pandemic and evaluate their binding affinity with ACE2. Evolutionary analysis of 2178 SARS-CoV2 genomes identifies RBD variants that are under selection bias. The binding efficacy of these RBD variants to the ACE2 has been analyzed by using protein-protein docking and binding free energy calculations. Pan-proteomic analysis reveals 113 mutations among them 33 are parsimonious. Evolutionary analysis reveals five RBD variants A348T, V367F, G476S, V483A, and S494P are under strong positive selection bias. Variations at these sites alter the ACE2 binding affinity. A348T, G476S, and V483A variants display reduced affinity to ACE2 in comparison to the Wuhan SARS-CoV2 spike protein. While the V367F and S494P population variants display a higher binding affinity towards human ACE2. Reorientation of several crucial residues at the RBD-ACE2 interface facilitates additional hydrogen bond formation for the V367F variant which enhances the binding energy during ACE2 recognition. On the other hand, the enhanced binding affinity of S494P is attributed to strong interfacial complementarity between the RBD and ACE2., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aristolochic acids (AAs) are a natural bioactive substance found in Chinese herbs, which are widely used for treating diseases. Many studies have demonstrated that AAs have various pharmacological function, while increasing reports indicated its toxicity. However, the role AAs in cognition remains poorly understood. This study explored the neurotoxic effect of aristolochic acid I (AAI), the most toxic component of the AAs family, on hippocampal synaptic plasticity and spatial cognition in mice. C57BL/6 mice were exposed to 5 mg/kg AAI for 4 weeks. After chronic treatment, AAI considerably increased the level of anxiety and the degree of behavioral despair in mice. Working and reference error rates were higher in the AAI exposed mice than in the control. This was further validated by the molecular docking studies, which AAI might interact with 5-HT 2 serotonin receptor (5-HT 2A R). Mechanism investigation indicated that AAI triggered inflammation in the hippocampus of mice through increasing the activity of Tnf-α-NF-κB-IL-6 signaling pathway. Conclusively, chronic AAI administration causes inflammation, and it possibly also serves as a potential antagonist of 5-HT 2A R to influence the cognition function in C57BL/6 mice., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In recent years, butyrylcholinesterase (BChE) has gradually gained worldwide interests as a novel target for treating Alzheimer's disease (AD). Here, two pharmacophore models were generated using Schrödinger suite and used to virtually screen ChemDiv database, from which three hits were obtained. Among them, 2513-4169 displayed the highest inhibitory activity and selectivity against BChE (eeAChE IC 50  > 10 μM, eqBChE IC 50  = 3.73 ± 1.90 μM). Molecular dynamic (MD) simulation validated the binding pattern of 2513-4169 in BChE, and it could form a various of receptor-ligand interactions with adjacent residues. In vitro cytotoxicity assay proved the safety of 2513-4169 on diverse neural cell lines. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay performed on SH-SY5Y cells proved the neuroprotective effect of 2513-4169 against toxic Aβ 1 - 42 . In vivo behavioral study further confirmed the great efficacy of 2513-4169 on reversing Aβ 1 - 42 -induced cognitive impairment of mice and clearing the toxic Aβ 1 - 42 in brains. Moreover, 2513-4169 was proved to be able to cross blood-brain barrier (BBB) through a parallel artificial membrane permeation assay of BBB (PAMPA-BBB). Taken together, 2513-4169 is a promising lead compound for future optimization to discover anti-AD treating agents., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020. Published by Elsevier B.V.)

This study aimed to reveal the interaction and inhibitory mechanisms of tangeretin (TAN), nobiletin (NBT), and their acidic hydroxylated forms, 5-demethyltangeretin (5-DT) and 5-demethylnobiletin (5-DN) on porcine pancreatic lipase (PPL) using spectroscopic techniques and molecular dynamics (MD) simulation. PPL inhibition assay showed that the inhibitory activity of NBT (IC 50 value of 3.60 ± 0.19 μM) was superior to those of three polymethoxylated flavones (PMFs), indicating it may be related to the methoxy groups at the 3'-position in its molecular structure. Inhibition kinetic analyses demonstrated that the inhibition types of the 4 PMFs were consistent with the mixed inhibition model, which agreed well with the results from the ultraviolet-visible (UV-Vis) spectroscopy, Circular dichroism (CD), fluorescence spectroscopy, molecular docking, and MD simulation that PMFs could bind to the PPL catalytic site and non-catalytic site, affecting the normal spatial conformation of PPL and weakening its ability to decompose the substrate. All these findings suggest that PMFs are a kind of natural lipase inhibitors, and NBT has the potential as a lipase inhibition precursor because of its unique flavone skeleton structure., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Chrysosplenetin is a methoxyflavone with reported anti-cancer effect. We tested its cytotoxic effect on the MCF-7 breast cancer cell line, and determined its effect on DNA intercalation and on the activity of topoisomerases I and II. The compound inhibited proliferation MCF-7 with an IC 50 value of 0.29 μM. Chrysosplenetin did not initiate plasmid DNA cleavage but, in a concentration-dependent manner, protected plasmid DNA against damage induced by Fenton reagents. Furthermore, it possessed dual Topoisomerase I and II inhibitory properties. Especially, it inhibited topoisomerase II by 83-96% between the range 12.5-100 μM. In the light of these experimental findings, molecular docking studies were performed to understand binding mode, interactions and affinity of chrysosplenetin with DNA, and with topoisomerases I and II. These studies showed that of 4-chromone core and the hydroxyl and methoxy groups important for both intercalation with DNA and topoisomerase I and II inhibition., Competing Interests: Declaration of competing interest The authors have declared that these are no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Glutathione S-transferases (GSTs) are multifunctional enzymes that play major roles in a wide range of biological processes, including cellular detoxification, biosynthesis, metabolism, and transport. The dynamic structural scaffold and diverse functional roles of GSTs make them important for enzyme engineering and for exploring novel biotechnological applications. The present study reported a significant gain-of-function activity in GST caused by a point mutation at the conserved F136 residue. The fluorescence quenching and kinetic data suggested that both binding affinity and catalytic efficiency of the mutant enzyme to the substrates 1-chloro-2,4-dinitrobenzene (CDNB), as well as the glutathione (GSH), is increased. Molecular docking showed that the mutation improves the binding interactions of the GSH with several binding-site residues. The simulation of molecular dynamics revealed that the mutant enzyme gained increased structural rigidity than the wild-type enzyme. The mutation also altered the residue interaction network (RIN) of the GSH-binding residues. These phenomena suggested that mutations led to conformational alterations and dominant differential motions in the enzyme that lead to increased rigidity and modifications in RIN. Collectively, engineering GST with a single point mutation at conserved F136 can significantly increase its xenobiotic activity by increasing the catalytic efficiency that may be exploited for biotechnological applications., Competing Interests: Declaration of competing interest The authors declare no conflict of interest exists., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this study, inhibitory kinetics of Nuciferine and Methyl Ganoderate extrated from Lotus Leaves and Ganoderma lucidum on Mucor miehei Lipase were studied first. The molecular structure of Nuciferine and Methyl Ganoderate were determined. The inhibitory effects of two extracts on lipase were reversible, with the IC 50 values of 0.194 and 0.332 mg/mL, respectively. The inhibition kinetic analysis by Lineweaver-Burk plots showed that they were a mixed-type inhibitor of lipase, with inhibition constants K I of 0.16 and 0.29 mg/mL, and K IS of 0.36 and 0.49 mg/mL, respectively. Results of spectral analysis showed that the UV absorption and the molecule fluorescence spectrum of the lipase hydrolyzate were significantly decreased after the inhibitor was added. The molecular docking further suggested that the interaction site between the active substance and inhibitor was located in an α-helix and a β-sheet of the lipase, and the lipase active site was interfered by the inhibitor near the cap structure. In addition, the proliferation and differentiation of 3 T3-L1 preadipocytes were inhibited by two extracts. Total triglycerides and cholesterol were significantly reduced in the cells. The results confirmed that Nuciferine and Methyl Ganoderate can be used as potential obesity treatment drugs., Competing Interests: Declaration of competing interest The authors report no declarations of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Epilobium is a medicinal plant; its extracts are widely used traditional medicine due to their broad range of pharmacological and therapeutic properties. Its most prominent feature is its therapeutic effects on prostatic diseases. The aim of this study is preparation of controlled release system of Epilobium parviflorum, and determination of its potential of anticancer applications. For this purpose, Epilobium parviflorum extract (EPE) loaded chitosan nanoparticles were prepared with ionic gelation method to increase the bioavailability of the extract. The nanoparticles were investigated in terms of size, zeta potential, polydispersity index, encapsulation efficiency, loading capacity and release profile. Besides, scanning electron microscopy (SEM) was used to observe the morphology of the nanoparticles. Moreover, Ames/Salmonella test was used to determine the mutagenicity of EPE, and it was shown that it had no mutagenic effect. It was found that EPE loaded chitosan nanoparticles were with 64.47 nm in average size, 0.168 PdI and 15.2 mV zeta potential. Encapsulation efficiency and loading capacity were found as 92.46% and 8%, respectively. Finally, DNA binding assay and in silico molecular docking studies were performed between EPE and DNA in order to contribute to design of plant based controlled release system for use in cancer therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Microtubule affinity regulating kinase (MARK4) is considered as a potential drug target for diabetes, cancer, and neurodegenerative diseases. Since the role of MARK4 in the phosphorylation of tau protein and subsequently Alzheimer's disease has been established, therefore, we have investigated the binding affinity and MARK4 inhibitory potential of cholic acid (CHA) using both computational and spectroscopic methods. Molecular docking suggested a strong binding of CHA to the functionally important residues of MARK4. We further performed 500 ns molecular dynamics simulation which suggested the MARK4-CHA system was quite stable throughout the simulation trajectory. CHA potential binds to the MARK4 with a binding constant (K) of 10 7  M -1 at 288 K. Further, MARK4 activity was inhibited by CHA with an IC 50  = 5.5 μM. Further insights into the thermodynamic parameters suggested that MARK4-CHA complex formation is driven by both electrostatic and van der Waals interactions. Overall study provides a rationale to use CHA in the drug development via MARK4 inhibition, towards possible therapeutic implications in neurodegenerative diseases., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Cyclin-dependent kinase 9 (CDK9) is a member of the CDK subfamily and plays a major role in the regulation of transcriptional elongation. It has attracted widespread attention as a therapeutic target for cancer. Here, we aimed to explore novel CDK 9 inhibitors by using a hybrid virtual screening strategy., Main Methods: A hybrid virtual screening strategy was constructed with computer-aided drug design (CADD). First, compounds were filtered in accordance with Lipinski's rule of five and adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Second, a 3D-QSAR pharmacophore model was built and used as a 3D query to screen the obtained hit compounds. Third, the hit compounds were subjected to molecular docking studies. Fourth, molecular dynamics (MD) simulations were performed on CDK9 in complex with the final hits to examine the structural stability. Finally, CDK9 kinase biochemical assay was performed to identify the biological activity of the hit compounds., Key Findings: Seven hit compounds were screened out. These hit compounds showed drug-like properties in accordance with Lipinski's rule of five and ADMET. Complexes involving the six hit compounds bound to CDK9 exhibited good structural stability in the MD simulation. Furthermore, these six hit compounds had strong inhibitory activity against CDK9 kinase. In particular, hit 3 showed the most promising activity with the percentage of 71%., Significance: The six hit compounds may be promising novel CDK9 inhibitors, and the hybrid virtual screening strategy designed in this study provides an important reference for the design and synthesis of novel CDK9 inhibitors., Competing Interests: Declaration of competing interest We declare that we have no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Inhibition of pancreatic lipase (PL) is considered one of the important therapeutic interventions against obesity. In the present study, the inhibition of porcine (mammalian) PL (PPL) by two tripeptides glutathione (GSH) and s-allyl glutathione (SAG) was studied. In vitro kinetic analysis was done to determine the inhibition of GSH and SAG against PPL. The binding of GSH and SAG with PPL was elucidated by fluorescence spectroscopy analysis. Docking and molecular dynamics (MD) simulation analysis was carried out to understand the intermolecular interaction between both GSH and SAG with PPL as well as human PL (HPL). Both GSH and SAG inhibited PPL in mixed non-competitive manner. The IC 50 value for GSH and SAG against PPL was found to be 2.97 and 6.4 mM, respectively. Both GSH and SAG quenched the intrinsic fluorescence of PPL through static quenching that is through forming complex with the PPL. SAG and GSH interacted with amino acids involved in catalysis of both PPL and HPL. MD simulation showed interactions of SAG and GSH with both PPL and HPL were stable. These results would lead to the further studies and application of GSH and SAG against obesity through inhibition of PL., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Multitarget-directed ligands are a promising class of drugs for discovering innovative new therapies for difficult to treat diseases. In this study, we designed dual inhibitors targeting the human fatty acid amide hydrolase (FAAH) enzyme and human soluble epoxide hydrolase (sEH) enzyme. Targeting both of these enzymes concurrently with single target inhibitors synergistically reduces inflammatory and neuropathic pain; thus, dual FAAH/sEH inhibitors are likely to be powerful analgesics. Here, we identified the piperidinyl-sulfonamide moiety as a common pharmacophore and optimized several inhibitors to have excellent inhibition profiles on both targeted enzymes simultaneously. In addition, several inhibitors show good predicted pharmacokinetic properties. These results suggest that this series of inhibitors has the potential to be further developed as new lead candidates and therapeutics in pain management., 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 © 2020 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the most common form of dementia. While drugs that target several pathways underlying AD have been proposed, effective treatments remain to be discovered. BACE1, an enzyme associated with AD progression, is a promising target for developing anti-Alzheimer drugs. To find novel multifunctional anti-Alzheimer agents, we designed and synthesized a series of new substituted benzyl-1H-1,2,3-triazol-4-yl-N-cyclohexylimidazo[1,2-a]pyridin-3-amine. The in vitro screening results revealed that most of the compounds exhibited moderate to potent BACE1 and BuChE inhibitory and antioxidant activities. Compounds 7f and 7g, bearing dichloro (2,3-Cl 2 and 3,4-Cl 2 ) moieties on the benzyl pendant were selected as the most active compounds in our BACE1 inhibitory assay with respective IC 50 values of about 12 and 8.9 μM. In addition, compounds 7g and 7h (4-bromo derivative) showed the highest BuChE inhibitory activity with IC 50 of 3.2 and 2.5 µM, respectively. Compound 7g also possessed antioxidant activity with an IC 50 value of 10.2 μM and metal chelation potential. Moreover, docking studies were performed to investigate the possible mechanism of inhibition. Taken together, we demonstrate that N-cyclohexylimidazo[1,2-a]pyridine containing triazole motif derivatives deserve further investigation for anti-Alzheimer drug development., 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 © 2020. Published by Elsevier Inc.)

In this study, the inhibitory effects of four anthraquinones including chrysophanol, emodin, physcione and rhein on tyrosinase were investigated by enzyme inhibition assay. The results indicated that all of anthraquinones could significantly inhibit the activity of tyrosinase in a competitive manner. To gain insight into the inhibitory mechanism of anthraquinones on tyrosinase, spectroscopic analysis combined with molecular docking studies were performed. Fluorescence results showed that anthraquinones interacted with tyrosinase by static quenching in a molecular ratio of 1:1. Circular dichroism and molecular docking suggested that anthraquinones could not chelate directly the copper ions but they could bind to amino acid residues in the active site of tyrosinase via electrostatic forces and hydrophobic interactions, as well as hydrogen bonds, and the binding processes resulted in the conformational changes of tyrosinase and prevented the substrate (L-DOPA) from entering the active site, which led to the decrease of tyrosinase activity. Our study in this paper provides a scientific basis for revealing the inhibition of tyrosinase activity by anthraquinone compounds. As a natural inhibitor of tyrosinase, anthraquinones can be used as a potential agent to reduce enzymatic browning reactions, such as food browning and melanization of skin., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Acetylcholinesterase has been a promising target for the development of putative therapeutics against cognitive decline. The deleterious effect of oxidative stress on the learning and memory paradigms of an individual has also been well documented. In view of this, the present study demonstrates the design, synthesis and pharmacological evaluation of triazole-oxadiazole conjugates. Eighteen novel hybrids (6-23) have been synthesised by employing suitable synthetic procedures and characterized by various spectral and elemental techniques. Further these synthesised compounds were evaluated against behavioural alterations using step down passive avoidance and escape learning protocol at a dose of 0.5 mg/kg with reference to the standard, donepezil. All the synthesised compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme. Biochemical estimation of markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione and catalase) has also been carried out to assess the role of synthesised molecules on the oxidative damage induced by scopolamine. The compounds 13, 17 and 23 displayed appreciable activity towards acetylcholinesterase inhibition. These compounds also decreased scopolamine induced oxidative stress, thus serving as promising leads for the amelioration of oxidative stress induced cognitive decline. The molecular docking study performed to predict the binding mode of the compounds also suggested that these compounds bind appreciably to the amino acids present in the active site of the recombinant human acetylcholinesterase (rhAChE). The results indicated that these compounds could be further traversed as inhibitors of AChE and oxidative stress for the treatment of cognitive dysfunction., 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 © 2020 Elsevier Inc. All rights reserved.)

The COVID-19 pandemic raised by SARS-CoV-2 is a public health emergency. However, lack of antiviral drugs and vaccine against human coronaviruses demands a concerted approach to challenge the SARS-CoV-2 infection. Under limited resource and urgency, combinatorial computational approaches to identify the potential inhibitor from known drugs could be applied against risen COVID-19 pandemic. Thereof, this study attempted to purpose the potent inhibitors from the approved drug pool against SARS-CoV-2 main protease (M pro ). To circumvent the issue of lead compound from available drugs as antivirals, antibiotics with broad spectrum of viral activity, i.e. doxycycline, tetracycline, demeclocycline, and minocycline were chosen for molecular simulation analysis against native ligand N3 inhibitor in SARS-CoV-2 M pro crystal structure. Molecular docking simulation predicted the docking score >-7 kcal/mol with significant intermolecular interaction at the catalytic dyad (His41 and Cys145) and other essential substrate binding residues of SARS-CoV-2 M pro . The best ligand conformations were further studied for complex stability and intermolecular interaction profiling with respect to time under 100 ns classical molecular dynamics simulation, established the significant stability and interactions of selected antibiotics by comparison to N3 inhibitor. Based on combinatorial molecular simulation analysis, doxycycline and minocycline were selected as potent inhibitor against SARS-CoV-2 M pro which can used in combinational therapy against SARS-CoV-2 infection., Competing Interests: Declaration of competing interest The author declares that there is no competing interest in this work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A small library of 3-thia-7,9-diazabicyclo[3.3.1]nonanes was synthesized and their opioid receptors affinity and selectivity evaluated. Among these novel sulfur-bridged compounds, the (E) 9-[3'-(3-chlorophenyl)-but-2'-en-1'-yl]-7-propionyl-3-thia-7,9-diazabicyclo[3.3.1]nonane 2i emerged as the derivative with the highest μ receptor affinity (K i  = 85 nM) and selectivity (K i μ/δ = 58.8, K i μ/κ > 117.6). The antinociceptive activity of 2i was also evaluated in acute thermal pain. Docking studies disclosed the specific pattern of interactions of these derivatives., 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 © 2020 Elsevier Inc. All rights reserved.)

In this work, we describe the design, synthesis and SAR studies of 2-benzylidenebenzofuran-3-ones (aurones), a new family of potent inhibitors of CK2. A series of aurones have been synthesized. These compounds are structurally related to the synthetic flavones and showed nanomolar activities towards CK2. Biochemical tests revealed that 20 newly synthesized compounds inhibited CK2 with IC 50 values in the nanomolar range. Further property-based optimization of aurones was performed, yielding a series of CK2 inhibitors with enhanced lipophilic efficiency. The most potent compound 12m (BFO13) has CLipE = 4.94 (CLogP = 3.5; IC 50  = 3.6 nM) commensurable with the best known inhibitors of CK2., 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 © 2020 Elsevier Inc. All rights reserved.)

The inhibition of cyclooxygenase-1 (COX-1) enzyme by Nonsteroidal anti-inflammatory drugs (NSAIDs) exposes the gastrointestinal mucosa to peptic injuries. Selective inhibition of COX-2 generates surpassing anti-inflammatory drug candidates with reduced side effects over current NSAIDs. Phytosterols consumption is reported to decrease the risk of cardiovascular problems. Reports on the selective inhibition of COX-2 by phytosterols are scarce. The present study assesses the anti-inflammatory potentials of phytosterols from Nicotiana tabacum (of the family Solanaceae) through selective inhibition of COX-1 and/or COX-2. Virtual High Throughput Screening (vHTS) and Molecular Docking of phytochemicals from Nicotiana tabacum against the catalytic pockets of COX-1 and COX-2 were used to identify the lead bioactive(s) components of the plant. The hit phytosterols were isolated, histopathological examination of the stomach, in-vivo COX-1/COX-2 mRNAs expression patterns in the liver through reverse transcription-polymerase chain reactions, and enzymes activities of Nicotiana tabacum phytosterol isolates (NTPI) in HCl/ethanol-induced inflammation in Wistar rats were all investigated. Formation of hydrogen bonds favour selective inhibition of COX-2 while hydrophobic interactions favour selective inhibition of COX-1. NTPI demonstrates inhibition of COX-2 by down-regulate the expression of COX-2 mRNA and were ineffective against the expression COX-1 mRNA. NTPI demonstrates hepatoprotective abilities by improving the antioxidant defense system of the liver. Histopathological analyses show NTPI at 50 mg/kg bodyweight regenerates the parietal cells and maintain the gastrointestinal architecture. Drug likeness prediction and ADME toxicity screening show that phytosterols possess good oral bioavailability with no side effects. Phytosterols are selective inhibitors of COX-2, they are hepatoprotective, regenerate parietal cells, and non-toxic., 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 © 2020 Elsevier Inc. All rights reserved.)

Poncirin, a natural flavanone glycoside present abundantly in many citrus fruits, contains an extensive range of biological activities. However, the antidiabetic mechanism of poncirin is unexplored yet. In this study, we examined the anti-diabetic prospective of poncirin by evaluating its ability to inhibit protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant AR (HRAR), rat lens aldose reductase (RLAR), and advanced glycation end-product (AGE) formation (IC 50  = 7.76 ± 0.21, 21.31 ± 1.26, 3.56 ± 0.33, 11.91 ± 0.21, and 3.23 ± 0.09 µM, respectively). Kinetics data and docking studies showed the lowest binding energy and highestaffinityforthemixed and competitivetypeof inhibitorsof poncirin. Moreover, the molecular mechanisms underlying the antidiabetic outcomes of poncirin in insulin resistant C2C12 skeletal muscle cells were explored, which significantly increased glucose uptake and decreased the expression of PTP1B in C2C12 cells. Consequently, poncirin increased GLUT-4 expression level by activating the IRS-1/PI3K/Akt/GSK-3 signaling pathway. Moreover, poncirin (0.5-50 µM) remarkably inhibited the formation of fluorescent AGE, nonfluorescent CML, fructosamine, and β-cross amyloid structures in glucose-fructose-induced BSA glycation during 4 weeks of study. Poncirin also notably prevented protein oxidation demonstrated with decreasing the protein carbonyl and the consumption of protein thiol in the dose-dependent manner. The results clearly expressed the promising activity of poncirin for the therapy of diabetes and its related complications., 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 © 2020 Elsevier Inc. All rights reserved.)

Diketopiperazines (DKPs) have been regarded as an important scaffold from the viewpoint of synthesis due to their biological properties for the treatment of several diseases, including cancer. In this work, two novel series of enantiomeric 2,6-DKPs derived from α-amino acids were synthesized through nucleophilic substitution and intramolecular cyclization reactions. All the compounds were docked against histone deacetylase 8 (HDAC8), which is a promising target for the development of anticancer drugs. These compounds bound into the active site of HDAC8 in a similar way to Trichostatin A (TSA), which is an HDAC8 inhibitor. This study showed that the conformation of the 2,6-DKP ring, stereochemistry, and the type of substituent on the chiral center had an important role in the binding modes. The Gibbs free energies and dissociation constants values of HDAC8-ligand complexes showed that compounds (S)-4hBn, (S)-4m, (R)-4h, and (R)-4m were more stable and affine towards HDAC8 than TSA. The inhibitory activities of 4a, (S)-4h, (S)- and (R)-4(g, l, m) were evaluated in vitro on HDAC8. It was found that compounds (R)-4g (IC 50  = 21.54 nM) and (R)-4m (IC 50  = 10.81 nM) exhibited better inhibitory activities than TSA (IC 50  = 28.32 nM). These results suggested that 2,6-DKPs derivatives may be promising anticancer agents for further biological 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 © 2020 Elsevier Inc. All rights reserved.)

Formation of the amyloid beta (Aβ) peptide aggregations represents an indispensable role in appearing and progression of Alzheimer disease. β-sheet breaker peptides can be designed and modified with different amino acids in order to improve biological properties and binding affinity to the amyloid beta peptide. In the present study, three peptide sequences were designed based on the hopeful results of LIAIMA peptide and molecular docking studies were carried out onto the monomer and fibril structure of amyloid beta peptide using AutoDock Vina software. According to the obtained interactions and binding energy from docking, the best-designed peptide (d-GABA-FPLIAIMA) was chosen and synthesized in great yield (%96) via the Fmoc solid-phase peptide synthesis. The synthesis and purity of the resulting peptide were estimated and evaluated by Mass spectroscopy and Reversed-phase high-performance liquid chromatography (RP-HPLC) methods, respectively. Stability studies in plasma and Thioflavin T (ThT) assay were performed in order to measure the binding affinity and in vitro aggregation inhibition of Aβ peptide. The d-GABA-FPLIAIMA peptide showed good binding energy and affinity to Aβ fibrils, high stability (more than 90%) in human serum, and a reduction of 20% in inhibition of the Aβ aggregation growth. Finally, the favorable characteristics of our newly designed peptide make it a promising candidate β-sheet breaker agent for further in vivo 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 © 2020 Elsevier Inc. All rights reserved.)

A series of Sulfonamide-based Schiff bases (E)-4-(benzylideneamino)-N-(6-methoxypyridazin-3-yl) benzenesulfonamide (3a-r) targeting Urease Inhibition was synthesized from sulphamethoxy pyridazine and substituted aldehydes. The prepared compounds were characterized by various spectroscopic techniques including FTIR, 1 HNMR, 13 CNMR, and spectrometric HRMS analysis. The most active agent (3g) bearing halogens and OH groups gave IC 50 value of 2.20 µM for urease inhibition against the standard Thiourea (IC 50  = 20.03 ± 2.06) and the overall trend within the series was 3g > 3n > 3p > 3j > 3q > 3h, 3o > 3l, 3r > 3k, 3m > 3a > 3d > 3e > 3f. Structure-activity relationship study established that the nature as well as the position of varying groups attached to aryl group had crucial roles in defining the urease inhibition activity. Additionally, in silico investigation was carried out which demonstrated that the compounds exhibit polar and apolar contacts with the crucial residues in the binding site of urease. The ADME analysis suggested all the synthesized compounds to be non-toxic, and likely to undergo passive gastrointestinal absorption. Taken together, the study suggests that the synthesized Sulfonamide-based Schiff bases derivatives may serve as potential hits as urease inhibitors., Competing Interests: Declaration of Competing Interest All the authors declare no conflict of Interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: Silibinin is the major component of flavonolignans complex mixture (Silymarin), which is obtained from Silybum marianum (L.) Gaertn. Despite several reports about silibinin, little is known about its effects on gastric diseases. Then, the present study aims to evaluate the silibinin effect against Helicobacter pylori infection, gastric tumor cells and immunomodulation., Main Methods: The anti-H. pylori effect was performed on 43504 and 43629 strains by minimum inhibitory concentration (MIC) determination, observing morphological alterations by scanning electron microscopy and in silico evaluation by molecular docking. Immunomodulatory activity (Interleukins-6 and 10, TNF-α and NO inhibition) was determined in H. pylori-stimulated macrophages and the cytotoxic activity on gastric adenocarcinoma cells prior and after metabolization by S9 fraction., Key Findings: Silibinin showed anti-H. pylori activity with MIC of 256 μg/mL, promoted important morphological changes in the bacterial cell wall, as blebs and clusters, suggesting interaction with Penicillin Binding Protein (PBP) subunits. Immunomodulatory potential was observed at 50 μg/mL with the inhibition of produced cytokines and NO by H. pylori-stimulated macrophages of 100% for TNF-ɑ, 56.83% for IL-6, and 70.29% for IL-10 and 73.33% for NO. Moreover, silibinin demonstrated significant cytotoxic activity on adenocarcinoma cells (CI 50 : 60.17 ± 0.95 μg/mL) with a higher selectivity index (SI: 1.52) compared to cisplatin. After metabolization silibinin showed an increase of cytotoxicity with a CI 50 six-fold decrease (10.46 ± 0.25)., Significance: The use of silibinin may become an important alternative tool in the prevention and treatment of H. pylori infection and, consequently, in gastric cancer., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A new series of thiosemicarbazones were designed and synthesized. Their structures were confirmed by spectral characterization and single crystal XRD studies. Compounds MTSC-2 and ETSC-3 crystallized in the orthorhombic crystal system with space group Pbc2 1 andPca2 1 respectively. Density functional theory computational studies were performed on MTSC-2 and ETSC-3 along with natural bond orbital analysis and Mulliken population analysis to study the structural and electronic properties of the thiosemicarbazones. The HOMOs of the two thiosemicarbazones are -5.2943 and -5.1133 eV respectively while the LUMOs are -1.6879 and -1.6398 eV respectively. The energy gap is 3.6064 and 3.4736 eV respectively. Molecular docking studies were performed to determine the binding mode of the thiosemicarbazones against β-tubulin. The theoretical studies were further supplemented with tubulin polymerization inhibition assay. All the four thiosemicarbazones proved effective in inhibiting the polymerization of α- and β-tubulin heterodimers into microtubules. The anticancer activity of these compounds showed their extreme potency against A549 and HepG2 cancer cell lines with IC 50 values of 0.051 - 0.189 µm and 0.042 - 0.136 µm respectively. Compound PTSC-4 showed the highest activity both against tubulin and the two cancer cell lines. This was in correlation with the theoretical studies. Hence, these four compounds, specifically PTSC-4, can be considered to be potential leads in the development of non-metallic anticancer agents., 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 © 2020 Elsevier Inc. All rights reserved.)

Novel Mannich base analogues of pyrrolo[3,4-d]pyridazinone 7a,b-13a,b are designed and synthesized as potential anti-inflammatory agents. The title compounds are obtained via convenient one-pot synthesis with good yields. Their structures and properties are described by spectroscopic techniques and elemental analyses. The aim of this study is to evaluate the inhibitory activity of the new derivatives against both cyclooxygenase isoforms COX1 and COX2 as well as their cytotoxicity. The results clearly indicate that the tested compounds 7a,b-13a,b are not toxic, all show better affinity towards isoform COX-2, and some of them act as selective COX-2 inhibitors. Moreover, every examined derivative of pyrrolo[3,4-d]pyridazinone demonstrates better inhibitory activity towards COX-2 and a superior COX-2/COX-1 selectivity ratio compared to the reference drug meloxicam. Molecular docking studies confirm that compounds 7a,b-13a,b preferably bind COX-2 and all of them bind to the active site of cyclooxygenase in a way very similar to meloxicam. Subsequently, taking into account that inflammation is strongly correlated with oxidative stress and both of these processes can potentiate each other, synthesized Mannich bases are evaluated for potential antioxidant activity. Most of the investigated derivatives reduce induced oxidative and nitrosative stress. Moreover, compounds 7a,b, 8a, 10a,b, 11b, 12a,b-13a,b protect chromatin from oxidative stress and decrease the number of DNA strand breaks caused by intracellular growth of free radicals. Finally, a study of the binding mechanism between compounds 7a,b-13a,b and bovine serum albumin (BSA) was carried out. According to spectroscopic and molecular docking studies, all examined derivatives interact with BSA, which suggests their potential long half-life in vivo., 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 © 2020 Elsevier Inc. All rights reserved.)

Estrogen Related Receptors (ERRs) are key regulators of energy homeostasis and play important role in the etiology of metabolic disorders, skeletal muscle related disorders, and neurodegenerative diseases. Among the three ERR isoforms, ERRα emerged as a potential drug target for metabolic and neurodegenerative diseases. Although ERRβ/γ selective agonist chemical tools have been identified, there are no chemical tools that effectively target ERRα agonism. We successfully engineered high affinity ERRα agonism into a chemical scaffold that displays selective ERRβ/γ agonist activity (GSK4716), providing novel ERRα/β/γ pan agonists that can be used as tools to probe the physiological roles of these nuclear receptors. We identified the structural requirements to enhance selectivity toward ERRα. Molecular modeling shows that our novel modulators have favorable binding modes in the LBP of ERRα and can induce conformational changes where Phe328 that originally occupies the pocket is dislocated to accommodate the ligands in a rather small cavity. The best agonists up-regulated the expression of target genes PGC-1α and PGC-1β, which are necessary to achieve maximal mitochondrial biogenesis. Moreover, they increased the mRNA levels of PDK4, which play an important role in energy homeostasis., 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 © 2020 Elsevier Inc. All rights reserved.)

Two series of novel morpholinopyrimidine derivatives were synthesized and screened for their in-vitro cytotoxic activity against 60 tumor cell line by the National Cancer Institute, USA. The in-vitro cytotoxic IC 50 values for the most active compounds 6e, 6g, and 6l against the most sensitive cell line leukemia SR were estimated (IC 50  = 0.76, 13.59, and 4.37 uM, respectively). To investigate their PI3K enzyme inhibition activity, the assay was done on Class IA (α, β, & δ) isoforms. The IC 50 values were very promising: compound [6e = 11.73 (α), 6.09 (β), 11.18 (δ)], compound [6g = 8.43 (α), 15.84 (β), 30.62 (δ)], and compound [6l = 13.98 (α), 7.22 (β), 10.94 (δ)], compared to the reference compound LY294002 = 6.28 (α), 4.51 (β), 4.60 (δ) uM, respectively. Moreover, cell cycle analysis and annexin V-FITC staining were done on Leukemia SR, there was arrest at G2/M phase and apoptosis was induced. Finally, docking study was performed to analyze the interactive mode of these derivatives in PI3Kα ATP-binding site. These outcomes proved that compounds 6e, 6g, and 6l are potential leads for further optimization as antileukemic agents., 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 © 2020 Elsevier Inc. All rights reserved.)

Novel series of 5-benzylidenethiazolidine-2,4-dione derivatives 4 a-c -8 a-f were designed, synthesized and evaluated for anticancer activity against HepG2, HCT-116 and MCF-7 cell lines. MCF-7 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 8 f was found to be the most potent derivative overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC 50  = 11.19 ± 0.8, 8.99 ± 0.7 and 7.10 ± 0.4 µM respectively. Compound 8 f exhibited lower activity than sorafenib, (IC 50  = 9.18 ± 0.6, 8.37 ± 0.7 and 5.10 ± 0.4 µM respectively), against HepG2 and HCT116 but exhibited nearly the same activity against MCF-7 cancer cell lines respectively. Also, this compound displayed lower activity than doxorubicin, (IC 50  = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 µM respectively), against HepG2 and HCT116 but nearly the same activity against MCF-7cell lines respectively. The most active derivatives 6 c,d,f,g and 8 a-f were evaluated for their inhibitory activities against VEGFR-2. The elongation of the structures to have distal moieties enhanced anticancer and VEGFR-2 inhibitory activities as in compounds 8 a-f . Among them, compounds 8 f was found to be the most potent derivative that inhibited VEGFR-2 at IC 50 value of 0.22 ± 0.02 µM, which is nearly the half as that of sorafenib IC 50 value (0.10 ± 0.02 µM). Furthermore, molecular design was performed to investigate their binding mode and affinities towards VEGFR-2 receptor. The data obtained from docking studies were highly correlated with that obtained from the biological screening., 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 © 2020 Elsevier Inc. All rights reserved.)

A novel series of pyrazoles and pyrazolo[1,5-a]pyrimidines bearing benzothiazole moiety were designed and synthesized. Chemical structures were confirmed by spectral data and elemental analyses. Nine compounds were selected and screened for their cytotoxic activity at the National Cancer Institute (NCI), USA against 60 cancer cell lines in a single dose assay. Compounds 4 and 5 exerted the most potent growth inhibitory activity against most cancer cell lines with growth inhibition (GI%) ranges from 44.86% to 84.59% and 31.20% to 52.36%, respectively. Consequently, they were further investigated through IC 50 determination using five dose MTT colorimetric assay against three sensitive cell lines, leukemia CCRF-CEM, non-small cell lung cancer HOP-92 and liver cancer Hep-G2. Compound 4 exhibited potent cytotoxic activity against the three tested cell lines with IC 50 16.34, 3.45 and 7.79 μM, respectively representing half potency, 3.5 folds potency and nearly equipotent to roscovitine. To investigate its mechanism of action, cell cycle analysis of compound 4 was conducted and showed that it induced cell cycle arrest at G2/M phase and apoptosis in HOP-92 cells. In correlation with the previous results, caspase-3 activation was tested and illustrated elevation in its concentration by nearly 14 folds than control. Besides, enzyme inhibition assay of compound 4 was evaluated towards two common antitumor targets namely KDM1 and CDK1 showing significant inhibitory activity with IC 50 0.096 and 0.078 μM, respectively., 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 © 2020 Elsevier Inc. All rights reserved.)

In continuation of our previous work on the investigation of CDK9 inhibitors bearing indole moiety for the discovery of novel anticancer agents, novel methylenehydrazine-1-carboxamide derivatives with (5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole scaffold were designed, synthesized, and evaluated for the CDK9 inhibitory activity and anticancer activity. Biological activity results demonstrated that most of these derivatives possessed good inhibitory on the kinase activity of CDK9 such as blocking its phosphorylation function and inhibiting HIV-1 transcription. Compound 12i was found to be the most potent CDK9 inhibitor and exhibited excellent anticancer activity against HepG2, A375, MCF-7, and A549, but low toxic on normal cells including HaCaT and MCF-10A. Further studies revealed that as a result of CDK9 inhibition and subsequent inhibition of phosphorylation at Serine 2 of the RNAPII CTD, the representative compound 12i dose-dependently increased cleaved PARP level, exerting its antiproliferative effect through induction of apoptosis in cancer cells. Finally, the molecular docking analysis implied that 12i had a good binding affinity with CDK9. In summary, 12i is a potent CDK9 inhibitor and can be considered as a good lead-candidate for developing potential anticancer drugs., 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 © 2020 Elsevier Inc. All rights reserved.)

We herein applied the four step-synthetic route to prepare the pyridazine core attached to the various N-aryl acetamides. By this approach, a new series of pyridazine-based compounds were synthesized, characterized and evaluated for their activities against α-glucosidase enzyme. In-vitro α-glucosidase assay established that twelve compounds are more potent than acarbose. Compound 7a inhibited α-glucosidase with the IC 50 value of 70.1 µM. The most potent compounds showed no cytotoxicity against HDF cell line. Molecular docking and kinetic studies were performed to determine the modes of interaction and inhibition, respectively., 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 © 2020 Elsevier Inc. All rights reserved.)

A library of 34 novel compounds based on a xanthine scaffold was explored in biological studies for interaction with adenosine receptors (ARs). Structural modifications of the xanthine core were introduced in the 8-position (benzylamino and benzyloxy substitution) as well as at N1, N3, and N7 (small alkyl residues), thereby improving affinity and selectivity for the A 2A AR. The compounds were characterized by radioligand binding assays, and our study resulted in the development of the potent A 2A AR ligands including 8-((6-chloro-2-fluoro-3-methoxybenzyl)amino)-1-ethyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (12d; K i human A 2A AR: 68.5 nM) and 8-((2-chlorobenzyl)amino)-1-ethyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (12h; K i human A 2A AR: 71.1 nM). Moreover, dual A 1 /A 2A AR ligands were identified in the group of 1,3-diethyl-7-methylxanthine derivatives. Compound 14b displayed K i values of 52.2 nM for the A 1 AR and 167 nM for the A 2A AR. Selected A 2A AR ligands were further evaluated as inactive for inhibition of monoamine oxidase A, B and isoforms of phosphodiesterase-4B1, -10A, which represent classical targets for xanthine derivatives. Therefore, the developed 8-benzylaminoxanthine scaffold seems to be highly selective for AR activity and relevant for potent and selective A 2A ligands. Compound 12d with high selectivity for ARs, especially for the A 2A AR subtype, evaluated in animal models of inflammation has shown anti-inflammatory activity. Investigated compounds were found to display high selectivity and may therefore be of high interest for further development as drugs for treating cancer or neurodegenerative diseases., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Five new iridoids, jatadomins A-E (1-5), together with six known analogues (6-11) and one known sesquiterpenoid (12), were isolated from the roots of Valeriana jatamansi Jones. Their structures were determined by analysis of their NMR, HRESIMS, and electronic circular dichroism calculations (ECD) data. The biological evaluation revealed that compounds 1-6 had anti-inflammatory activities by inhibiting nitric oxide (NO) release in LPS-induced murine microglial BV-2 cells, with IC 50 values of 24.4, 9.2, 21.2, 25.9, 30.6, and 0.4 μM, respectively. Further molecular docking studies revealed a potential mechanism for NO inhibition by the bioactive compounds., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Multi-targeted anticancer drugs are in focus as a promising research topic. A new series of benzothiazoles hybridized with pyrimidine moiety was designed and synthesized using the lead compound 4a. Various chemical modifications on the pyrimidine ring of 4a at four different positions were done in a trial to get new multi-targeted anticancer agents. The structures of the newly synthesized compounds were established on their elemental analyses and spectral data. All final synthesized derivatives were submitted to the National Cancer Institute (NCI), USA, to be screened for their in vitro anticancer activity. Further evaluation for the cytotoxic activity of the most active compounds was performed using the MTT assay method. Compounds 4d, 8d, 8h, 8i and 17 were then selected for examining their in vitro enzyme inhibitory activities against EGFR, HER2 and TS enzymes using lapatinib and 5FU as standards. Furthermore, cell cycle analysis and apoptosis induction detection were also evaluated. Finally, molecular docking studies were carried out for compounds 4d, 8d, 8h, 8i and 17 to interpret their observed enzymatic activities based on the ligand-protein interactions., (Copyright © 2020 Elsevier Inc. All rights reserved.)