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Acetylcholinesterase (AChE), one of the major therapeutic strategies for the treatment of Alzheimer's disease (AD) is to increase the acetylcholine (ACh) level in the brain by inhibiting the biological activity of AChE. In this present work, a set of alkaloids and flavonoids against AChE enzyme were screened by computational chemistry techniques. The docking results showed that among alkaloid compounds the oxindole alkaloid namely mitragynine oxidole B (MITOB) and the indole alkaloids namely mitragynine (MIT) exhibited a good binding affinity towards AChE. These two compounds were then studied by molecular dynamics (MD) simulations. The binding free energy calculation and ligand-protein binding pattern suggested that both alkaloids could interact with AChE very well. Since MIT is the main alkaloid constituent of Mytragyna speciose leaves, this compound was isolated from M. speciose leaves and tested for anti-AChE activity. As a result, the isolated MIT had an inhibitory activity with pIC50 value of 3.57. This finding provided that the mitragynine compound has the potential to be as a therapeutic agent for further anti-AChE drug development in treatment of Alzheimer's disease.

The Janus kinase (JAK) and epidermal growth factor receptor (EGFR) have been considered as potential targets for cancer therapy due to their role in regulating proliferation and survival of cancer cells. In the present study, the aromatic alkyl-amino analogs of thiazole-based chalcone were selected to experimentally and theoretically investigate their inhibitory activity against JAK2 and EGFR proteins as well as their anti-cancer effects on human cancer cell lines expressing JAK2 (TF1 and HEL) and EGFR (A549 and A431). In vitro cytotoxicity screening results demonstrated that the HEL erythroleukemia cell line was susceptible to compounds 11 and 12, whereas the A431 lung cancer cell line was vulnerable to compound 25. However, TF1 and A549 cells were not sensitive to our thiazole derivatives. From kinase inhibition assay results, compound 25 was found to be a dual inhibitor against JAK2 and EGFR, whereas compounds 11 and 12 selectively inhibited the JAK2 protein. According to the molecular docking analysis, compounds 11, 12 and 25 formed hydrogen bonds with the hinge region residues Lys857, Leu932 and Glu930 and hydrophobically came into contact with Leu983 at the catalytic site of JAK2, while compound 25 formed a hydrogen bond with Met769 at the hinge region, Lys721 near a glycine loop, and Asp831 at the activation loop of EGFR. Altogether, these potent thiazole derivatives, following Lipinski's rule of five, could likely be developed as a promising JAK2/EGFR targeted drug(s) for cancer therapy.

Graphical abstract, The 3C-like main protease of SARS-CoV-2 (3CLPro) is responsible for the cleavage of the viral polyprotein. This process is essential for the viral life cycle. Therefore, 3CLPro is a promising target to develop antiviral drugs for COVID-19 prevention and treatment. Traditional enzymatic assays for the identification of 3CLPro inhibitors rely on peptide-based colorimetric or fluorogenic substrates. However, the COVID-19 pandemic has limit or delay access to these substrates, especially for researchers in developing countries attempting to screen natural product libraries. We explored the use of the fluorescent probe 8-anilinonaphthalene-1-sulfonate (ANS) as an alternative assay for inhibitor identification. Fluorescence enhancement upon binding of ANS to 3CLPro was observed, and this interaction was competitive with a peptide substrate. The utility of ANS-based competitive binding assay to identify 3CLPro inhibitors was demonstrated with the flavonoid natural products baicalein and rutin. The molecular nature of ANS and rutin interaction with 3CLPro was explored with molecular modeling. Our results suggested that ANS could be employed in a competitive binding assay to facilitate the identification of novel SARS-CoV-2 antiviral compounds.

(−)-Kusunokinin performed its anticancer potency through CFS1R and AKT pathways. Its ambiguous binding target has, however, hindered the next development phase. Our study thus applied molecular docking and molecular dynamics simulation to predict the protein target from the pathways. Among various candidates, aldo-keto reductase family 1 member B1 (AKR1B1) was finally identified as a (−)-kusunokinin receptor. The predicted binding affinity of (−)-kusunokinin was better than the selected aldose reductase inhibitors (ARIs) and substrates. The compound also had no significant effect on AKR1B1 conformation. An intriguing AKR1B1 efficacy, with respect to the known inhibitors (epalrestat, zenarestat, and minalrestat) and substrates (UVI2008 and prostaglandin H2), as well as a similar interactive insight of the enzyme pocket, pinpointed an ARI equivalence of (−)-kusunokinin. An aromatic ring and a γ-butyrolactone ring shared a role with structural counterparts in known inhibitors. The modeling explained that the aromatic constituent contributed to π–π attraction with Trp111. In addition, the γ-butyrolactone ring bound the catalytic His110 using hydrogen bonds, which could lead to enzymatic inhibition as a consequence of substrate competitiveness. Our computer-based findings suggested that the potential of (−)-kusunokinin could be furthered by in vitro and/or in vivo experiments to consolidate (−)-kusunokinin as a new AKR1B1 antagonist in the future.

Human topoisomerase II alpha (TopoIIα) is a crucial enzyme involved in maintaining genomic integrity during the process of DNA replication and mitotic division. It is a vital therapeutic target for designing novel anticancer agents in targeted cancer therapy. Sulfones, members of organosulfur compounds, have been reported to possess various biological activities such as antimicrobial, anti-inflammatory, anti-HIV, anticancer, and antimalarial properties. In the present study, a series of sulfones was selected to evaluate their inhibitory activity against TopoIIα using computational approaches. Molecular docking results revealed that several sulfone analogs bind efficiently to the ATPase domain of TopoIIα. Among them, sulfones 18a, 60a, *4 b, *8 b, *3c, and 8c exhibit higher binding affinity than the known TopoII inhibitor, salvicine. Molecular dynamics simulations and free energy calculations based on MM/PB(GB)SA method demonstrated that sulfone *8 b strongly interacts with amino acid residues in the ATP-binding pocket (E87, N91, D94, I125, I141, F142, S149, G161, and A167), driven mainly by an electrostatic attraction and a strong H-bond formation at G161 residue. Altogether, the obtained results predicted that sulfones could have a high potential to be a lead molecule for targeting TopoIIα.Communicated by Ramaswamy H. Sarma.

Drug-resistant Pseudomonas aeruginosa efflux pump extrudes antibiotics from cells for survival. Efflux pump inhibitor (EPI) thus becomes an interesting alternative to handle the drug-resistant bacteria. Conessine, a natural steroidal alkaloid from Holarrhena antidysenterica, previously exhibited efflux pump inhibitory potential. Our molecular docking and molecular dynamics (MD) studies provided atomistic information as well as the interaction of conessine with bacterial MexB efflux pump in phospholipid bilayer membrane to further the previous experimental report. Herein, the binding site and proposed mode of action of conessine were identified compared to known/commercial EPIs such as PAβN or designed-synthetic P9D. Our results explained conessine binding mode of action as an effective agent against the MexB efflux pump. The MD simulation also suggested that conessine was able to affect glycine loop (G-loop) flexibility, and the reduced G-loop flexibility due to conessine could hinder an antibiotics extrusion. In addition, our study suggested the conessine core structure buried in a hydrophobic region in the efflux pump similar to other known EPIs. Our finding could cope as a key for the design and development of the conessine derivative as novel EPI against P. aeruginosa.Communicated by Ramaswamy H. Sarma.

Human sweet taste receptor (hSTR) recognizes a wide array of sweeteners, resulting in sweet taste perception. Maltitol and lactitol have been extensively used in place of sucrose due to their capability to prevent dental caries. Herein, several molecular modeling approaches were applied to investigate the structural and energetic properties of these two polyols/hSTR complexes. Triplicate 500 ns molecular dynamics (MD) simulations and molecular mechanics/generalized Born surface area (MM/GBSA)-based free energy calculations revealed that the TAS1R2 monomer is the preferential binding site for maltitol and lactitol rather than the TAS1R3 region. Several polar residues (D142, S144, Y215, D278, E302, R383, and especially N143) were involved in polyols binding through electrostatic attractions and H-bond formations. The molecular complexation process not only induced the stable form of ligands but also stimulated the conformational adaptation of the TAS1R2 monomer to become a close-packed structure through an induced-fit mechanism. Notably, the binding affinity of the maltitol/TAS1R2 complex (ΔGbind of -17.93 ± 1.49 kcal/mol) was significantly higher than that of the lactitol/TAS1R2 system (-8.53 ± 1.78 kcal/mol), in line with the experimental relative sweetness. These findings provide an in-depth understanding of the differences in the sweetness response between maltitol and lactitol, which could be helpful to design novel polyol derivatives with higher sweet taste perception.

Activated carbon (AC) was prepared from waste tea (WT) and the obtained product, WTAC, was modified with ethylenediamine (MWTAC). Unmodified and modified WTAC samples were characterized in terms of structural, morphological and chemical properties. Carbon dioxide (CO2) adsorptions from pure CO2 and swine farm biogas of WT, WTAC and MWTAC were investigated to determine the effect of activation and modification as well as the effect of methane in real swine farm biogas on the CO2 adsorption performances. The adsorption capacities of pure CO2 on the WT, WTAC and MWTAC were 15.39, 87.42 and 108.97 mg/g, respectively, while the adsorption capacities of 40% CO2 from swine farm biogas were 4.22, 60.64 and 78.98 mg/g, respectively, indicating that modified AC leads to a higher CO2 adsorption capacity. In addition, density functional theory (DFT) calculations revealed that the adsorption energies for graphene + CO2, unmodified AC + CO2 and modified AC + CO2 models were −7.53, −50.74 and −65.21 kJ/mol, respectively, indicating the modified AC model led to a higher adsorption than that of the unmodified AC and graphene models, owning to hydrogen bond and dispersion interactions between the CO2 molecule and more active atoms on the surface of the modified AC model.

A flavonoid is a versatile core structure with various cellular, immunological, and pharmacological effects. Recently, flavones have shown anti-dengue activities by interfering with viral translation and replication. However, the molecular target is still elusive. Here we chemically modified apigenin by adding an alkyne moiety into the B-ring hydroxyl group. The alkyne serves as a chemical tag for the alkyne-azide cycloaddition reaction for subcellular visualization. The compound located at the perinuclear region at 1 and 6 h after infection. Interestingly, the compound signal started shifting to vesicle-like structures at 6 h and accumulated at 24 and 48 h after infection. Moreover, the compound treatment in dengue-infected cells showed that the compound restricted the viral protein inside the vesicles, especially at 48 h. As a result, the dengue envelope proteins spread throughout the cells. The alkyne-tagged apigenin showed a more potent efficacy at the EC50 of 2.36 ± 0.22, and 10.55 ± 3.37 µM, respectively, while the cytotoxicities were similar to the original apigenin at the CC50 of 70.34 ± 11.79, and 82.82 ± 11.68 µM, respectively. Molecular docking confirmed the apigenin binding to the previously reported target, ribosomal protein S9, at two binding sites. The network analysis, homopharma, and molecular docking revealed that the estrogen receptor 1 and viral NS1 were potential targets at the late infection stage. The interactions could attenuate dengue productivity by interfering with viral translation and suppressing the viral proteins from trafficking to the cell surface.

Metal nanomaterials can enhance the efficacy of current cancer therapies. Here, we show that Ti0.8O2 nanosheets cause cytotoxicity in several lung cancer cells but not in normal cells. The nanosheet-treated cells showed certain apoptosis characteristics. Protein analysis further indicated the activation of the p53-dependent death mechanism. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) analyses revealed the cellular uptake of the nanosheets and the induction of cell morphological change. The nanosheets also exhibited a substantial apoptosis effect on drug-resistant metastatic primary lung cancer cells, and it was found that the potency of the nanosheets was dramatically higher than standard drugs. Ti0.8O2 nanosheets induce apoptosis through a molecular mechanism involving peroxynitrite (ONOO−) generation. As peroxynitrite is known to be a potent inducer of S-nitrosylation, we further found that the nanosheets mediated the S-nitrosylation of p53 at C182, resulting in higher protein-protein complex stability, and this was likely to induce the surrounding residues, located in the interface region, to bind more strongly to each other. Molecular dynamics analysis revealed that S-nitrosylation stabilized the p53 dimer with a ΔGbindresidue of &lt, −1.5 kcal/mol. These results provide novel insight on the apoptosis induction effect of the nanosheets via a molecular mechanism involving S-nitrosylation of the p53 protein, emphasizing the mechanism of action of nanomaterials for cancer therapy.

Influenza epidemics are responsible for an average of 3-5 millions of severe cases and up to 500,000 deaths around the world. One of flu pandemic types is influenza A(H1N1)pdm09 virus (pdm09H1N1). Oseltamivir is the antiviral drug used to treat influenza targeting at neuraminidase (NA) located on the viral surface. Influenza virus undergoes high mutation rates and leads to drug resistance, and thus the development of more efficient drugs is required. In the present study, all-atom molecular dynamics simulations were applied to understand the oseltamivir resistance caused by the single E119D and double E119D/H274Y mutations on NA. The obtained results in terms of binding free energy and intermolecular interactions in the ligand-protein interface showed that the oseltamivir could not be well accommodated in the binding pocket of both NA mutants and the 150-loop moves out from oseltamivir as an "open" state. A greater number of water molecules accessible to the binding pocket could disrupt the oseltamivir binding with NA target as seen be high mobility of oseltamivir at the active site. Additionally, our finding could guide to the design and development of novel NA inhibitor drugs.

Luteolin (LL) and pinocembrin (PB) are plant-derived flavonoids predominantly found in many fruits and vegetables showing several biological effects, especially an antioxidant activity. However, the low water solubility of these two compounds limits their use in many pharmaceutical applications. Beta-cyclodextrin (βCD) and its derivatives (e.g., methylated (M) and hydroxypropylated (HP) βCDs) have been extensively used to enhance the stability and solubility of many hydrophobic guest molecules through an encapsulation process into the lipophilic inner cavity. In the present study, the dynamics behavior and the stability of inclusion complexes of two flavonoids LL and PB with βCDs were studied using all-atom molecular dynamics simulations and MM/PB(GB)SA free energy calculations. The obtained results showed that the van der Waals driven encapsulation of LL and PB could adapt the structure of the βCDs to become more stable conformers via an enhanced intramolecular hydrogen bond formation on the secondary rim. The structural data and free energy results demonstrated that the phenyl orientation was the preferred binding mode for LL and PB inclusion complexations. In addition, βCD derivatives, especially HPβCDs, could significantly enhance the stability of both flavonoids better than natural βCD.

The effect of microsolvation on excited-state proton transfer (ESPT) reaction of 3-hydroxyflavone (3HF) and its inclusion complex with γ-cyclodextrin (γ-CD) was studied using computational approaches. From molecular dynamics simulations, two possible inclusion complexes formed by the chromone ring (C-ring, Form I) and the phenyl ring (P-ring, Form II) of 3HF insertion to γ-CD were observed. Form II is likely more stable because of lower fluctuation of 3HF inside the hydrophobic cavity and lower water accessibility to the encapsulated 3HF. Next, the conformation analysis of these models in the ground (S0) and the first excited (S1) states was carried out by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations, respectively, to reveal the photophysical properties of 3HF influenced by the γ-CD. The results show that the intermolecular hydrogen bonding (interHB) between 3HF and γ-CD, and intramolecular hydrogen bonding (intraHB) within 3HF are strengthened in the S1 state confirmed by the shorter interHB and intraHB distances and the red-shift of O–H vibrational modes involving in the ESPT process. The simulated absorption and emission spectra are in good agreement with the experimental data. Significantly, in the S1 state, the keto form of 3HF is stabilized by γ-CD, explaining the increased quantum yield of keto emission of 3HF when complexing with γ-CD in the experiment. In the other word, ESPT of 3HF is more favorable in the γ-CD hydrophobic cavity than in aqueous solution.

The emergence outbreak caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has received significant attention on the global risks. Due to itscrucial role in viral replication, the main protease 3CLpro is an important target for drug discovery and development to combat COVID-19. In this work, the structural and dynamic behaviors as well as binding efficiency of the four peptidomimetic inhibitors (N3, 11a, 13b, and 14b) recently co-crystalized with SARS-CoV-2 3CLpro were studied and compared using all-atom molecular dynamics (MD) simulations and solvated interaction energy-based binding free energy calculations. The per-residue decomposition free energy results suggested that the key residues involved in inhibitors binding were H41, M49, L141–C145, H163–E166, P168, and Q189–T190 in the domains I and II. The van der Waals interaction yielded the main energy contribution stabilizing all the focused inhibitors. Besides, their hydrogen bond formations with F140, G143, C145, H164, E166, and Q189 residues in the substrate-binding pocket were also essential for strengthening the molecular complexation. The predicted binding affinity of the four peptidomimetic inhibitors agreed with the reported experimental data, and the 13b showed the most efficient binding to SARS-CoV-2 3CLpro. From rational drug design strategies based on 13b, the polar moieties (e.g., benzamide) and the bulky N-terminal protecting groups (e.g., thiazole) should be introduced to P1’ and P4 sites in order to enhance H-bonds and hydrophobic interactions, respectively. We hope that the obtained structural and energetic information could be beneficial for developing novel SARS-CoV-2 3CLpro inhibitors with higher inhibitory potency to combat COVID-19., Graphical abstract Unlabelled Image, Highlights • The four recent peptidomimetic inhibitors were investigated using MD simulations and free energy calculations. • The key residues involved in inhibitors binding are H41, M49, L141–C145, H163–E166, P168, and Q189–T190. • The van der Waals interaction yielded the main energy contribution stabilizing all studied inhibitors. • The 13b is chosen as a template for structural modifications to gain more interactions with the surrounding amino acids.

Background: Neuraminidase (NA), a major glycoprotein found on the surface of the influenza virus, is an important target for the prophylaxis and treatment of influenza virus infections. Recently, several plant-derived polyphenols, especially caffeic acid analogs, have been reported to exert the inhibitory activity against NA. Objective: Herein, we aimed to investigate the anti-influenza NA activity of caffeic acid and its hydroxycinnamate analogues, rosmarinic acid and salvianolic acid A, in comparison to a known NA inhibitor, oseltamivir. Methods: In vitro MUNANA-based NA inhibitory assay was used to evaluate the inhibitory activity of the three interested hydroxycinnamic compounds towards the influenza NA enzyme. Subsequently, allatom molecular dynamics (MD) simulations and binding free energy calculations were employed to elucidate the structural insights into the protein-ligand complexations. Results: Rosmarinic acid showed the highest inhibitory activity against NA with the IC50 of 0.40 μM compared to caffeic acid (IC50 of 0.81 μM) and salvianolic acid A (IC50 of >1 μM). From 100-ns MD simulations, the binding affinity, hot-spot residues, and H-bond formations of rosmarinic acid/NA complex were higher than those of caffeic acid/NA model, in which their molecular complexations was driven mainly by electrostatic attractions and H-bond formations from several charged residues (R118, E119, D151, R152, E227, E277, and R371). Notably, the two hydroxyl groups on both phenyl and phenylacetic rings of rosmarinic acid play a crucial role in stabilizing NA through a strongly formed Hbond( s). Conclusion: Our findings shed light on the potentiality of rosmarinic acid as a lead compound for further development of a potential influenza NA inhibitor.

&alpha, Mangostin (MGS) exhibits various pharmacological activities, including antioxidant, anticancer, antibacterial, and anti-inflammatory properties. However, its low water solubility is the major obstacle for its use in pharmaceutical applications. To increase the water solubility of MGS, complex formation with beta-cyclodextrins (&beta, CDs), particularly with the native &beta, CD and/or its derivative 2,6-dimethyl-&beta, CD (DM&beta, CD) is a promising technique. Although there have been several reports on the adsorption of &beta, CDs on the lipid bilayer, the release of the MGS/&beta, CDs inclusion complex through the biological membrane remains unclear. In this present study, the release the MGS from the two different &beta, CDs (&beta, CD and DM&beta, CD) across the lipid bilayer was investigated. Firstly, the adsorption of the free MGS, free &beta, CDs, and inclusion complex formation was studied by conventional molecular dynamics simulation. The MGS in complex with those two &beta, CDs was able to spontaneously release free MGS into the inner membrane. However, both MGS and DM&beta, CD molecules potentially permeated into the deeper region of the interior membrane, whereas &beta, CD only adsorbed at the outer membrane surface. The interaction between secondary rim of &beta, CD and the 1-palmitoeyl-2-oleoyl-glycero-3-phosphocholine (POPC) phosphate groups showed the highest number of hydrogen bonds (up to 14) corresponding to the favorable location of &beta, CD on the POPC membrane. Additionally, the findings suggested that electrostatic energy was the main driving force for &beta, CD adsorption on the POPC membrane, while van der Waals interactions played a predominant role in DM&beta, CD adsorption. The release profile of MGS from the &beta, CDs pocket across the lipid bilayer exhibited two energy minima along the reaction coordinate associated with the permeation of the MGS molecule into the deeper region of the POPC membrane.

Emodin (ED), one prominent variant of naturally occurring anthraquinones traditionally used in Chinese medicine, exhibits a wide spectrum of pharmacological properties. However, the poor aqueous solubility of ED limits its significant usage in practical applications. β-cyclodextrin (βCD) and its derivatives have been extensively utilized to enhance the water solubility and stability of lipophilic guest molecules by acting as a molecular shield through host-guest encapsulation. In this work, the structural dynamics details of inclusion complexation of ED with βCD and its two derivatives: 2-hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutylether-β-cyclodextrin (SBEβCD), were studied using all-atom molecular dynamics (MD) simulations and molecular mechanics/generalized Born surface area (MM/GBSA)-based binding free energy (ΔGbind) calculations. The 500-ns MD simulations revealed that ED is able to form inclusion complexes with βCDs in two possible orientations: resorcinol ring insertion (R-form) and m-cresol ring insertion (C-form) mainly driven by van der Waals interaction. The ED/SBEβCD inclusion complex showed the highest number of atom contacts and the lowest solvent accessibility at the hydrophobic cavity, in line with the ΔGbind results ranked in the order of ED/SBEβCD (−6.18 ± 1.15 kcal/mol) > ED/HPβCD (−3.81 ± 0.65 kcal/mol) > ED/βCD (0.11 ± 0.51 kcal/mol). All findings suggested that βCD derivatives, especially SBEβCD, could be the appropriate host for ED in the potential development of ED into pharmaceutical applications.

Genistein is an isoflavone with promising pharmaceutical applications. However, its low water solubility interferes with its potency, and therefore cyclodextrins (CDs) have been considered as possible drug delivery system (DDS). To investigate the complexation mechanism of genistein in cyclodextrin, we employed molecular dynamics (MD) simulations based on classical potentials and the density-functional tight-binding (DFTB) quantum chemical potential. Both classical and quantum chemical MD simulations predict that the phenol ring of genistein is preferentially complexed in the cavity of CD. The complexation process reduces the water-accessible solvation shell, and it is found that a hydrogen bond is formed between genistein and CD. The DFTB-based MD simulations reveal that spontaneous keto-enol tautomerization occurs even within a hundred picoseconds, which suggests that the encapsulated genistein is complexed in the ordinary enol form of the drug molecule. Analyses of the molecular charge distributions suggest that electrostatic interactions partially induce the complex formation, rather than extensive formation of hydrogen bonds.

Daidzein is an isoflavone of the group of phytoestrogens extracted from soybeans and other legumes. As its structure is relatively similar to that of the hormone estrogen, daidzein is able to bind with estrogen receptors leading to a reduced postmenopausal women symptom. A common problem of the compounds of this group is the rather low water solubility with the consequence of limited pharmaceutical applications. Inclusion complexation between daidzein and two β-CDs (β-CD and DM-β-CD) was investigated by theoretical and experimental techniques. Based on multiple MD simulations in combination with different binding-free energy calculations, the most preferential mode of daidzein binding to cyclodextrins is the insertion of the chromone ring fitting well into the hydrophobic cavity. All four methods of binding-free energy calculations (MM/PBSA, MM/GBSA, QM/PBSA, and QM/GBSA) predict the binding affinity of the daidzein/DM-β-CD complex significantly higher than the daidzein/β-CD. Following the same trend, the experimental results also indicated the enhancement of solubility and stability of the daidzein/DM-β-CD complex. Moreover, it was found that the complexation process was favorably enthalpy driven.

The structural dynamics and stability of inclusion complexes of mansonone E (ME) and H (MH) including their stereoisomers with various βCDs (methylated- and hydroxypropylated-βCDs) were investigated by classical molecular dynamics (MD) simulations and binding free energy calculations. The simulation results revealed that mansonones are able to form inclusion complexes with βCDs. The guest molecules are not completely inserted into the host cavity, their preferably positions are nearby the secondary rim with the oxane ring dipping into the hydrophobic inner cavity. The encapsulation process leads to a higher rigidity of the βCDs enhancing the intramolecular hydrogen bond formation ability and decreasing the chance of glucopyranose rotation. According to the MM-PBSA binding free energy calculation, all considered inclusion complexes are stable and the binding energies are mainly caused by van der Waals interactions. Moreover, the free energy calculations showed significant differences in the complexation energies for the stereoisomers, which could enable the separation of the isomers by analytical techniques for further pharmaceutical applications.

Atomistic molecular dynamics (MD) simulation of the inclusion complexes formation between scandenin, a phytochemical compound found in D. scandens, and five different types of cyclodextrin (CD); β-cyclodextrin (βCD), 2-hydroxypropyl βCD (2-HPβCD), 6-hydroxypropyl βCD (6-HPβCD), 2,6-dimethyl βCD (2,6-DMβCD), and 2,6-dihydroxypropyl βCD (2,6-DHPβCD) were carried out via two possible orientations of the guest molecule. The simulated results revealed that scandenin preferentially located within all the studied βCDs nanocavities by inserting its hydroxyphenyl ring and pyran terminal close to the narrow and wider rims (conf-A), respectively. In another feasible orientation (conf-B), the guest substance was deeply included into the lipophilic cavity of only 6-HPβCD and 2,6-DMβCD, but not in the other cyclodextrins. The favored inclusion formation of scandenin/2,6-DHPβCD occurred when the guest interpolated its hydroxyphenyl terminal into CD hydrophobic interior. Binding free energy calculation based on the MM-PBSA approach indicated that the modified βCDs (except for 2,6-DHPβCD) showed the stronger binding affinity to scandenin than did the parent host molecule. The results could help in selecting suitable βCD derivatives to enhance the stability of such guest molecules prior to in vitro testing.

2-Acetyl-1-pyrroline (2AP) is a key volatile compound contributing to a characteristic popcorn-like odor in several Asian aromatic rice varieties. Even though a demand for 2AP has been continuously increasing in global markets, its instability is a significant problem for commercial and food applications. Beta-cyclodextrin (βCD) has been extensively used to improve the stability, solubility, and sensorial properties of many hydrophobic and volatile compounds via an encapsulation process into its hydrophobic inner cavity. In this work, molecular complexation between 2AP and βCDs (hydroxypropyl (HP) and methyl (M) analogs) was theoretically and experimentally investigated using molecular dynamics (MD) simulation, molecular mechanics/generalized Born surface area-based free energy calculation, and gas chromatography–mass spectrometry (GC–MS). Triplicate 500 ns MD simulations revealed that, among six studied βCDs, only 6-HPβCD and 2,6-DMβCD derivatives could stably form inclusion complexes with 2AP, driven mainly by van der Waals interactions. The pyrroline ring of 2AP was preferentially embedded in the hydrophobic interior of 2,6-DMβCD, whereas the pyrroline and acetyl moieties of 2AP were freely rotated inside 6-HPβCD along the simulation times. The binding affinity, the compactness, and the number of atomic contacts of 2AP/2,6-DMβCD complex were higher than those of 2AP/6-HPβCD system, in good agreement with the highest remaining 2AP in the 2AP/2,6-DMβCD complex from GC–MS result. Altogether, the obtained theoretical and experimental data demonstrated the good potentiality of 2,6-DMβCD as suitable host molecule for 2AP encapsulation.

Several quinone-based metabolites of anticancer drugs and naturally occurring quinone-containing compounds have been characterized as potent inhibitors toward topoisomerase IIα (TopoIIα), an essential enzyme involved in maintaining genomic integrity during DNA replication and mitotic division. Mansonone G (MG), a naphthoquinone-containing compound extracted from the heartwood of Mansonia gagei , exhibits various biological activities including antitumor potential. In the present study, MG and its semi-synthetic derivatives were selected to study the preferential binding site and dynamics behavior as well as to predict the inhibitory activity against TopoIIα using molecular modeling approaches. The molecular docking results revealed that the entire series of MG preferentially target to the ATPase domain. Among all studied MGs, the ester derivative MG14 containing C-10 length exhibited the highest binding affinity against TopoIIα and greater than that of the ATP-competitive inhibitor salvicine as well as 1,4-benzoquinone. Interestingly, the MG14 binding could induce the closed form of the turn region (residues 147–151) inside ATP-binding pocket, implying that this event might be one of the crucial mechanisms underlying TopoIIα inhibition. The obtained theoretical information is useful as rational guide for further development of new anticancer agents containing naphthoquinone moiety against TopoIIα.

Enzyme I (EI) of bacterial phosphotransferase system is involved in the first step of the carbohydrate metabolism pathway. Due to its importance in bacterial survival and low similarity with human proteins, EI is an attractive drug target. With the aid of Computer Aided Drug Designing tools, we studied EI of Staphylococcus epidermidis, which recently adopted itself as a major etiological agent in discerning the cause of multi-drug resistant nosocomial infections of implanted medical devices. Due to a non-existent crystal structure, a high quality homology model of EI is predicted. Molecular docking analysis of potential inhibitors into the active site of the protein is performed and the best inhibitor is selected with according to the highest GoldScore (76.53). The protein-ligand complex was conducted through a 100 ns MD simulation. The trajectory analysis reveals that the N-terminal domain (EIN) and the P-His domain residues exhibited the greatest conformational changes while the active site shows minimum residual fluctuations and is considered as the most stable domain. The rigid body motions of EIN and P-His domain are recorded to be at their highest during the 35th and 83rd ns with highest RMSD values. Despite the highly flexible ‘personality’ of EI, the ligand remains tightly associated with the active site residues. The current lead compound holds potential as an effective drug against S. epidermidis which could be further tested in clinical settings. The dynamic nature of EI disclosed via MD simulation, can be further explored to understand the molecular kinetics of chemical reactions involved in the dedicated role of the protein would assist in better design of drugs in future.

The inclusion complexation of neral, a cis-isomer of citral found in lemon grass (Cymbopogon citratus Stapf), and four different types of cyclodextrin (β-cyclodextrin (βCD), 2,6-dimethyl-βCD (2,6DM...

Density functional theory (DFT) calculations have been carried out to investigate the ethylene insertion pathway using a Ziegler-Natta catalyst in the absence and presence of electron donor (ED) systems on the (1 1 0) MgCl 2 surface. The coadsorptions of four different EDs i.e. Si(OEt) m Cl n ( m + n = 4) were investigated. The presence of Si(OEt) 4 on the (1 1 0) MgCl 2 surface with the preferential bidentate mode was found to have the strongest adsorption energy (Δ E ads ). The potential energy surface (PES) map indicated that the reaction mechanism of the ethylene insertion into the Ti C bond on the (1 1 0) Mg 13 Cl 26 .TiCl 3 -CH 2 CH 3 surface is pseudo-concerted. As the differences in the intrinsic activation energies (Δ E a ) obtained from all systems are so small, this energy cannot be used to fully explain the significant changes in the rates of the ethylene insertion reaction observed when an ED is employed. Here, the apparent activation energy (ΔΔ E aa ) was calculated using the PBE functional and the 6-31G(d, p) basis set for C, H, O, Mg and Cl, and the LANL2DZ basis set with an ECP function for the Ti atom. All EDs presented in this work in the ethylene insertion reaction can significantly reduce the apparent energy barrier when compared to an absence of any ED system. The obtained ΔΔ E aa for the four ED complexes were found to decrease in the following order: SiOEtCl 3 > Si(OEt) 2 Cl 2 > Si(OEt) 3 Cl > Si(OEt) 4 . The obtained data lead to the conclusion that Si(OEt) 4 is the most suitable ED to increase the productivity of PE in the presence of alkoxysilane.

Avicequinone C (5a), a furanonaphthoquinone isolated from the Thai mangrove Avicennia marina has been shown previously to have interesting steroid 5α-reductase type 1 inhibitory activity. In this study, a series of avicequinone C analogues containing furanonaphthoquinone with different degrees of saturation and substituents at the furan ring were synthesized. The resulting synthetic avicequinone C and analogues (5a-f) along with some related compounds including 2,5-dihydroxy-1,4-benzoquinone (6) and natural naphthoquinones such as lawsone (7a) and lapachol (7b) were evaluated for their in vitro cell viability and steroid 5α-reductase type 1 inhibitory activities using the cultured cell line of human keratinocytes (HaCaT). This cell-based bioassay was performed based on a direct detection of the enzymatic product dihydrotestosterone (2) by using a non-radioactive high performance thin layer chromatography (HPTLC) method. Among the furanonaphthoquinones in this series, 5e having a propionic substituent at furan ring possessed approximately 22-fold more potent than the original isolated compound 5a. However, the compounds without furan motif such as 6, 7a and b could not inhibit the activity of steroid 5α-reductase. Molecular docking results of the in silico three-dimensional steroid 5α-reductase type 1-reduced nicotinamide adenine dinucleotide phosphate (NADPH) binary complex was performed via AutoDock Vina and it illustrated that the furanonaphthoquinone moiety and the substituent at furan ring might play a key role as pharmacophores for the steroid 5α-reductase inhibitory activity.

The human T1R2-T1R3 sweet taste receptor (STR) plays an important role in recognizing various low-molecular-weight sweet-tasting sugars and proteins, resulting in the release of intracellular heterotrimeric G protein that in turn leads to the sweet taste perception. Xylitol and sorbitol, which are naturally occurring sugar alcohols (polyols) found in many fruits and vegetables, exhibit the potential caries-reducing effect and are widely used for diabetic patients as low-calorie sweeteners. In the present study, computational tools were applied to investigate the structural details of binary complexes formed between these two polyols and the T1R2-T1R3 heterodimeric STR. Principal component analysis revealed that the Venus flytrap domain (VFD) of T1R2 monomer was adapted by the induced-fit mechanism to accommodate the focused polyols, in which residues 233–268 moved significantly closer to stabilize ligands. This finding likely suggested that these structural transformations might be the important mechanisms underlying polyols-STR recognitions. The calculated free energies also supported the VFD of T1R2 monomer as the preferential binding site for such polyols, rather than T1R3 region, in accord with the lower number of accessible water molecules in the T1R2 pocket. The E302 amino acid residue in T1R2 was found to be the important recognition residue for polyols binding through a strongly formed hydrogen bond. Additionally, the binding affinity of xylitol toward the T1R2 monomer was significantly higher than that of sorbitol, making it a sweeter tasting molecule.

Human cytosolic serine hydroxymethyltransferase (hcSHMT) is a promising target for anticancer chemotherapy and contains a flexible “flap motif” whose function is yet unknown. Here, using size-exclusion chromatography, analytical ultracentrifugation, small-angle X-ray scattering (SAXS), molecular dynamics (MD) simulations, and ligand-binding and enzyme-kinetic analyses, we studied the functional roles of the flap motif by comparing WT hcSHMT with a flap-deleted variant (hcSHMT/Δflap). We found that deletion of the flap results in a mixture of apo-dimers and holo-tetramers, whereas the WT was mostly in the tetrameric form. MD simulations indicated that the flap stabilizes structural compactness and thereby enhances oligomerization. The hcSHMT/Δflap variant exhibited different catalytic properties in (6S)-tetrahydrofolate (THF)-dependent reactions compared with the WT but had similar activity in THF-independent aldol cleavage of β-hydroxyamino acid. hcSHMT/Δflap was less sensitive to THF inhibition than the WT (K(i) of 0.65 and 0.27 mm THF at pH 7.5, respectively), and the THF dissociation constant of the WT was also 3-fold lower than that of hcSHMT/Δflap, indicating that the flap is important for THF binding. hcSHMT/Δflap did not display the burst kinetics observed in the WT. These results indicate that, upon removal of the flap, product release is no longer the rate-limiting step, implying that the flap is important for controlling product release. The findings reported here improve our understanding of the functional roles of the flap motif in hcSHMT and provide fundamental insight into how a flexible loop can be involved in controlling the enzymatic reactions of hcSHMT and other enzymes.

Targeted cancer therapy has become a high potential cancer treatment. Epidermal growth factor receptor (EGFR), which plays an important role in cell signaling, enhanced cell survival and proliferation, has been suggested as molecular target for the development of novel cancer therapeutics. In this study, a series of chalcone derivatives was screened by in vitro cytotoxicity against the wild type (A431 and A549) and mutant EGFR (H1975 and H1650) cancer cell lines, and, subsequently, tested for EGFR-tyrosine kinase (TK) inhibition. From the experimental screening, all chalcones seemed to be more active against the A431 than the A549 cell line, with chalcones 1c, 2a, 3e, 4e, and 4t showing a more than 50% inhibitory activity against the EGFR-TK activity and a high cytotoxicity with IC50 values of &lt, 10 &micro, M against A431 cells. Moreover, these five chalcones showed more potent on H1975 (T790M/L858R mutation) than H1650 (exon 19 deletion E746-A750) cell lines. Only three chalcones (1c, 2a and 3e) had an inhibitory activity against EGFR-TK with a relative inhibition percentage that was close to the approved drug, erlotinib. Molecular dynamics studies on their complexes with EGFR-TK domain in aqueous solution affirmed that they were well-occupied within the ATP binding site and strongly interacted with seven hydrophobic residues, including the important hinge region residue M793. From the above information, as well as ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, all three chalcones could serve as lead compounds for the development of EGFR-TK inhibitors.

Secretory diarrhea is one of the most common causes of death world-wide especially in children under 5 years old. Isoliquiritigenin (ISLQ), a plant-derived chalcone, has previously been shown to exert anti-secretory action in vitro and in vivo by inhibiting CFTR Cl− channels. However, its CFTR inhibition potency is considerably low (IC50 > 10 μM) with unknown mechanism of action. This study aimed to identify novel chalcone derivatives with improved potency and explore their mechanism of action. Screening of 27 chalcone derivatives identified CHAL-025 as the most potent chalcone analog that reversibly inhibited CFTR-mediated Cl− secretion in T84 cells with an IC50 of ∼1.5 μM. As analyzed by electrophysiological and biochemical analyses, the mechanism of CFTR inhibition by CHAL-025 is through AMP-activated protein kinase (AMPK), a negative regulator of CFTR activity. Furthermore, Western blot analyses and molecular dynamics (MD) results suggest that CHAL-025 activates AMPK by binding at the allosteric site of an upstream kinase calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ). Interestingly, CHAL-025 inhibited both cholera toxin (CT) and bile acid-induced Cl− secretion in T84 cells and prevented CT-induced intestinal fluid secretion in mice. Therefore, CHAL-025 represents a promising anti-diarrheal agent that inhibits CFTR Cl− channel activity via CaMKKβ-AMPK pathways. Keywords: Diarrhea, CFTR, Chalcone, AMPK, Chloride secretion

Glycerophosphodiesterase (GpdQ) from Enterobacter aerogenes is a binuclear metallohydrolase, which is capable of catalyzing the hydrolysis of mono-, di-, and tri-ester substrates, including some organophosphate pesticides and degradation products of nerve agents. The GpdQ has attracted recent attention as a promising enzyme for bioremediation. This enzyme utilizes two metal ions located in the α and β sites of the enzyme active site for catalysis and is found to bind to Fe(II) ion preferentially. In this study, we aimed to investigate the binding interactions of three organophosphate pesticides (i.e., profenofos, diazinon and chlorpyrifos) to the GpdQ using computational approaches. Firstly, each pesticide molecule was separately docked into the active site of the GpdQ using molecular docking. Then, 500-ns MD simulations were carried out on the systems without (apo enzyme) and with pesticides bound. The MD results showed that the Feβ binds well with the GpdQ active site in the presence of pesticide. It is also seen that the binding of the pesticide could stabilize the enzyme structure in the active conformation, allowing the substrate to be catalysed into less harmful products. Therefore, the ability of in silico analysis presented here could be informative for enhancing enzyme stability and activity in the future.

Influenza is a respiratory contagious disease infecting people all around the globe. The Center for Disease Control and Prevention had estimated that from 1 October 2018 to 4 May 2019, there have been about 40 million flu patients, in which about 50 thousand cases have died. Many subtypes of influenza have developed drug resistance due to high mutation rates. Neuraminidase (NA) is the glycoprotein on the virus particle surface. Its function is to cleave the glycosidic bond with the sialic acid, leading the new virus to be able to infect other uninfected cells. Therefore, it is a promising protein target for drug design and development. The E276D and R292K NA mutations in the H10N4 influenza virus have been reported to cause drug resistance. In this study, molecular dynamics simulations and free energy calculations were applied to study the source of oseltamivir resistance in E276D, R292K, and E276D/R292K NA strains. The obtained results suggested that all studied mutants reduced the number of contact atoms, interaction energies, H-bonds, per-residue interaction energies, and total binding free energies towards the oseltamivir binding, resulting in a lower susceptibility. Only the interactions at residues 118, 119, and 371 were maintained in stabilizing the oseltamivir. The opening at 150- and 430-loops in E276D and double mutations caused the drug unbinding from the active site, increasing water accessibility into the binding pocket of NA enzyme.

The intrinsic properties and catalytic performances of single- and double-transition metals on graphitic carbon nitride, TMn@g-C3N4 (n = 1,2), toward the O2 activation were investigated by DFT calculation. The 3d-TM atoms are firmly trapped inside g-C3N4 which prevents the metal clustering and shows high thermodynamic stability. The dimetal-dioxygen adsorption configuration of the O2/TM2@g-C3N4 promotes electron transfer from catalyst to the adsorbed O2, which improves their catalytic performances over the O2/TM@g-C3N4. We observed the two different electron transfer mechanisms for O2 activation on TMn@g-C3N4, in which the double-metal acts as an electron donor while the single-metal acts as the bridge for electron transfer from the substrate to the adsorbed O2. Remarkably, the catalytic performance of the TMn@g-C3N4 for O2 dissociation has a strong correlation with the three factors, (i) the charge gained on adsorbed O2, (ii) the O2 adsorption energy, and (iii) the O-O distance. The Fe2@g-C3N4 as a low-cost and non-precious metal catalyst shows the best catalytic performance with the lowest activation energy barrier of 0.26 eV for O2 activation, and therefore, is predicted as a potential catalyst for O2 consuming reactions. Our finding provides useful information for further design and development of high efficient few-atom catalysts based 2D-carbon materials.

There is experimental evidence from adsorption and permeation studies that methane can enter the Zeolitic Imidazolate Framework (ZIF)-90 framework despite the fact that the critical diameter of methane (3.8 A) is larger than the window size of ZIF-90 (3.5 A) assuming a rigid framework. Therefore, adsorption and diffusion of methane in the ZIF-90 were investigated by Molecular Dynamics (MD) and Gibbs Ensemble Monte Carlo. Various interaction force fields have been tested and a suitable one has been proposed. Results of structural and dynamical properties of methane in ZIF-90 are presented. Like for methane in ZIF-8, no gate opening was found in this paper for methane in ZIF-90 up to a pressure of 260 bar. Therefore, the adsorption and diffusion of methane in ZIF-90 can be explained by a flexible framework.

In the present study, we describe here the pH condition activating doxorubicin (DOX) anticancer drugs loading and release over single-wall carbon nanotube (SWNT) non-covalently wrapped with chitosan (CS). The possibility of drug displacement on DOX/CS/SWNT nanocarrier was investigated using molecular dynamics simulations. The drug loading and release were monitored via displacement analysis and binding energy calculations. The simulated results clearly showed that the drugs well interacted with the CS/SWNT at physiological pH (pH 7.4), where CS was in the deprotonated form. Contrastingly, in weakly acidic environments (pH 5.0-6.5) which is a pH characteristics of certain cancer environments, the protonated CS became loosen wrapped around the SWNT and triggered drugs release as a result of charge-charge repulsion between CS and drug molecules. The obtained data fulfil the understanding at atomic level of drug loading and release controlled by pH-sensitive polymer, which might be useful for further cancer therapy researches.

A study on the molecular conformation and electronic properties of different degrees of polymerisation of emeraldine salt polyaniline (ES PANI) has been explored using ab-initio calculations in order to have an insight into the optoelectronic properties, such as band gap, molecular orbital distribution, and UV–visible absorption spectrum conductivity mechanism. The optimization was done with DFT and TD-DFT for calculated UV-visible spectrum using B3LYP/6–31 g(d,p) basis set. Systematic conformational search has been done to find the suitable monomer and dimer model of ES PANI. The monomer model tends to keep a coplanar conformation for π-π interaction where a dimer structure ES PANI has the twist angle between two central rings about 63 degrees. The UV-vis absorption spectrum has one peak in the visible range. A significant red-shift with more degree of polymerisation has the better prediction of experimental UV-visible spectrum.

Photophysical properties of the smallest o-hydroxy Schiff base, 2-(iminomethyl)phenol (IMP), were elucidated using B3LYP and RI-ADC(2) methods. Cis-enol is the most stable conformation in ground state. Potential energy profiles show that enol-keto tautomerization occurs with a small barrier. However, isomerization from cis- to trans-keto is not possible because of a high barrier. The trans-keto tautomer is only accessible through a conical intersection (CI) after excited-state intramolecular proton transfer (ESIPT). Dynamics results show that cis-enol undergoes ultrafast ESIPT to give cis-keto. Regions of CI may be initiated to yield keto forms through radiativeless process with torsion twist of about 40–50°.

Steroid 5α-reductase type II is a membrane-associated enzyme in an oxidoreductase family. This enzyme, which is found in male sexual organs, plays the important biological actions toward steroid metabolism. Overexpression of 5α-reductase type II has affected the balance between testosterone and dihydrotestosterone, which implicates the androgenic disorders, including prostate cancer, hirsutism, and androgenic alopecia. Lack of single-crystal X-ray structures of 5α-reductase has hindered mechanistic understanding and delayed the discovery and development of an effective inhibitor. Herein, we illustrated a comparative structure of 5α-reductase type II that derived from the homology modeling, employing a membrane-bound protein, isoprenylcysteine carboxyl methyltransferase as a homologous template. A catalytic pocket and the transmembrane site were identified. The resulting in silico structure was validated via Ramachandran plot and confirmed by docking studies of 30 known 5α-reductase type I and type II inhibitors, including finasteride and dutasteride. The comparative docking study of the derived in silico 5α-reductase type II and 5β-reductase, a reported surrogate enzyme, was conducted. Our homology model approximately fitted to the membrane-associated character and showed the reasonable docking results, which depicted the well-defined comparative three-dimensional structure applicable for steroid reductase drug design.

Dengue infection is one of the most deleterious public health concerns for two-billion world population being at risk. Plasma leakage, hemorrhage, and shock in severe cases were caused by immunological derangement from secondary heterotypic infection. Flavanone, commonly found in medicinal plants, previously showed potential as anti-dengue inhibitors for its direct antiviral effects and suppressing the pro-inflammatory cytokine from dengue immunopathogenesis. Here, we chemically modified flavanones, pinocembrin and pinostrobin, by halogenation and characterized them as potential dengue 2 inhibitors and performed toxicity tests in human-derived cells and in vivo animal model. Dibromopinocembrin and dibromopinostrobin inhibited dengue serotype 2 at the EC50s of 2.0640 &plusmn, 0.7537 and 5.8567 &plusmn, 0.5074 &micro, M with at the CC50s of 67.2082 &plusmn, 0.9731 and &gt, 100 &micro, M, respectively. Both of the compounds also showed minimal toxicity against adult C57BL/6 mice assessed by ALT and Cr levels in day one, three, and eight post-intravenous administration. Computational studies suggested the potential target be likely the NS5 methyltransferase at SAM-binding pocket. Taken together, these two brominated flavanones are potential leads for further drug discovery investigation.

Topoisomerase IIα enzyme (Topo IIα) plays a critical function in DNA replication process and is considered to be a promising target of anti-cancer drugs. In the present study, we reported that the altholactone derivatives modified by adding a halogenated benzoate group showed greater inhibitory activity on Topo IIα enzyme in cell-free system concomitant with cytotoxicity against the CCA cell lines (KKU-M055 and KKU-M213) than those of the parent altholactone. However, the cytotoxic activities of four halogenated benzoate altholactone derivatives including iodo-, fluoro-, chloro-, and bromobenzoate derivatives (compound 1, 2, 3, and 4, respectively) were of equal potency. The fluorobenzoate derivative (compound 2) was chosen for investigating the underlying mechanism in CCA cells. Compound 2 arrested CCA cell cycle at sub G1 phase and induced apoptotic cell death. It markedly inhibited Topo IIα protein expression in both KKU-M055 and KKU-M213 cells, which was accompanied by DNA double-strand breaks demonstrated by an increase in phosphorylated H2A.X protein. Interestingly, KKU-M055 cells, which express higher Topo IIα mRNA compared to KKU-M213 cells, showed greater sensitivity to the compound, indicating the selectivity of the compound to Topo IIα enzyme. By computational docking analysis, the binding affinity of altholactone (-52.5 kcal/mol) and compound 2 (-56.7 kcal/mol) were similar to that of the Topo II poison salvicine (-53.7 kcal/mol). The aromatic moiety of both altholactones embedded in a hydrophobic pocket of Topo II ATPase domain. In addition, compound 2 induced the formation of linear DNA in Topo II-mediated cleavage assay. Collectively, our results demonstrate that the addition of fluorobenzoyl group to altholactone enhances potency and selectivity to inhibit type IIα topoisomerases. Atholactone and fluorobenzoate derivative act as Topo II cleavage complexes stabilizing compounds or Topo II poisons preferentially through binding at ATPase domain of Topo IIα, leading to DNA double-strand breaks and apoptosis induction. Such activity of 3-fluorobenzoate derivative of altholactone should be further explored for the development of an anti-cancer drug for CCA.

Low visibility on expressways caused by heavy fog and haze is a main reason for traffic accidents. Real-time estimation of atmospheric visibility is an effective way to reduce traffic accident rates. With the development of computer technology, estimating atmospheric visibility via computer vision becomes a research focus. However, the estimation accuracy should be enhanced since fog and haze are complex and time-varying. In this paper, a total bounded variation (TBV) approach to estimate low visibility (less than 300 m) is introduced. Surveillance images of fog and haze are processed as blurred images (pseudo-blurred images), while the surveillance images at selected road points on sunny days are handled as clear images, when considering fog and haze as noise superimposed on the clear images. By combining image spectrum and TBV, the features of foggy and hazy images can be extracted. The extraction results are compared with features of images on sunny days. Firstly, the low visibility surveillance images can be filtered out according to spectrum features of foggy and hazy images. For foggy and hazy images with visibility less than 300 m, the high-frequency coefficient ratio of Fourier (discrete cosine) transform is less than 20%, while the low-frequency coefficient ratio is between 100% and 120%. Secondly, the relationship between TBV and real visibility is established based on machine learning and piecewise stationary time series analysis. The established piecewise function can be used for visibility estimation. Finally, the visibility estimation approach proposed is validated based on real surveillance video data. The validation results are compared with the results of image contrast model. Besides, the big video data are collected from the Tongqi expressway, Jiangsu, China. A total of 1,782,000 frames were used and the relative errors of the approach proposed are less than 10%.

Targeted cancer therapy has become one of the high potential cancer treatments. Human topoisomerase II (hTopoII), which catalyzes the cleavage and rejoining of double-stranded DNA, is an important molecular target for the development of novel cancer therapeutics. In order to diversify the pharmacological activity of chalcones and to extend the scaffold of topoisomerase inhibitors, a series of chalcones was screened against hTopoIIα by computational techniques, and subsequently tested for their in vitro cytotoxicity. From the experimental IC50 values, chalcone 3d showed a high cytotoxicity with IC50 values of 10.8, 3.2 and 21.1 µM against the HT-1376, HeLa and MCF-7 cancer-derived cell lines, respectively, and also exhibited an inhibitory activity against hTopoIIα-ATPase that was better than the known inhibitor, salvicine. The observed ligand–protein interactions from a molecular dynamics study affirmed that 3d strongly interacts with the ATP-binding pocket residues. Altogether, the newly synthesised chalcone 3d has a high potential to serve as a lead compound for topoisomerase inhibitors.

The aim of this work is to improve physical properties and biological activities of the two flavanones hesperetin and naringenin by complexation with β-cyclodextrin (β-CD) and its methylated derivatives (2,6-di-O-methyl-β-cyclodextrin, DM-β-CD and randomly methylated-β-CD, RAMEB). The free energies of inclusion complexes between hesperetin with cyclodextrins (β-CD and DM-β-CD) were theoretically investigated by molecular dynamics simulation. The free energy values obtained suggested a more stable inclusion complex with DM-β-CD. The vdW force is the main guest–host interaction when hesperetin binds with CDs. The phase solubility diagram showed the formation of a soluble complex of AL type, with higher increase in solubility and stability when hesperetin and naringenin were complexed with RAMEB. Solid complexes were prepared by freeze-drying, and the data from differential scanning calorimetry (DSC) confirmed the formation of inclusion complexes. The data obtained by the dissolution method showed that complexation with RAMEB resulted in a better release of both flavanones to aqueous solution. The flavanones-β-CD/DM-β-CD complexes demonstrated a similar or a slight increase in anti-inflammatory activity and cytotoxicity towards three different cancer cell lines. The overall results suggested that solubilities and bioactivities of both flavanones were increased by complexation with methylated β-CDs.

Cyclodextrins (CDs) have been extensively utilized as host molecules to enhance the solubility, stability and bioavailability of hydrophobic drug molecules through the formation of inclusion complexes. It was previously reported that the use of co-solvents in such studies may result in ternary (host:guest:co-solvent) complex formation. The objective of this work was to investigate the effect of ethanol as a co-solvent on the inclusion complex formation between α-mangostin (α-MGS) and β-CD, using both experimental and theoretical studies. Experimental phase-solubility studies were carried out in order to assess complex formation, with the mechanism of association being probed using a mathematical model. It was found that α-MGS was poorly soluble at low ethanol concentrations (0–10% v/v), but higher concentrations (10–40% v/v) resulted in better α-MGS solubility at all β-CD concentrations studied (0–10 mM). From the equilibrium constant calculation, the inclusion complex is still a binary complex (1:1), even in the presence of ethanol. The results from our theoretical study confirm that the binding mode is binary complex and the presence of ethanol as co-solvent enhances the solubility of α-MGS with some effects on the binding affinity with β-CD, depending on the concentration employed.

The binding affinity of oseltamivir to the influenza B neuraminidase and to its variants with three single substitutions, E119G, R152K, and D198N, is investigated by the MM/3D-RISM method. The binding affinity or the binding free energy of ligand to receptor was found to be determined by a subtle balance of two major contributions that largely cancel out each other: the ligand-receptor interactions and the dehydration free energy. The theoretical results of the binding affinity of the drug to the mutants reproduced the observed trend in the resistivity, measured by IC50 ; the high-level resistance of E119G and R152K, and the low-level resistance of D198N. For E119G and R152K, reduction of the direct drug-target interaction, especially at the mutated residue, is the main source of high-level oseltamivir resistance. This phenomenon, however, is not found in the D198N strain, which is located in the framework of the active-site.

DNA topoisomerase I (Top1) catalyzes changes in DNA topology by cleaving and rejoining one strand of the double stranded (ds)DNA. Eukaryotic Top1s are the cellular target of the plant-derived anticancer indole alkaloid camptothecin (CPT), which reversibly stabilizes the Top1-dsDNA complex. However, CPT-producing plants, including Camptotheca acuminata , Ophiorrhiza pumila and Ophiorrhiza liukiuensis , are highly resistant to CPT because they possess point-mutated Top1. Here, the adaptive convergent evolution is reported between CPT production ability and mutations in their Top1, as a universal resistance mechanism found in all tested CPT-producing plants. This includes Nothapodytes nimmoniana , one of the major sources of CPT. To obtain a structural insight of the resistance mechanism, molecular dynamics simulations of CPT– resistant and –sensitive plant Top1s complexed with dsDNA and topotecan (a CPT derivative) were performed, these being compared to that for the CPT-sensitive human Top1. As a result, two mutations, Val617Gly and Asp710Gly, were identified in O. pumila Top1 and C. acuminata Top1, respectively. The substitutions at these two positions, surprisingly, are the same as those found in a CPT derivative-resistant human colon adenocarcinoma cell line. The results also demonstrated an increased linker flexibility of the CPT–resistant Top1, providing an additional explanation for the resistance mechanism found in CPT-producing plants. These mutations could reflect the long evolutionary adaptation of CPT-producing plant Top1s to confer a higher degree of resistance.

Electron donors enhance the productivity and isotacticity of products of the Ziegler–Natta catalyzed propylene polymerization. Using the fact that adsorption energies of electron donors to catalyst surface are linearly related to activities, the Quantitative Structure Property Relationship (QSPR) for adsorption energies was performed for a set of 24 compounds from 3 different groups, i.e., phthalates, 1,3-diethers and malonates using the multiple linear regression (MLR) analysis. The QSPR model shows high correlation ( R 2 = 0.84, R 2 CV = 0.83) between adsorption energies and 3 descriptors, i.e., the radius of gyration (50%), the dipole moment (16%), and the forcite bond energy (34%). Consequently, the catalyst activity of propylene polymerization mainly depended on steric hindrance. The predictive ability of the model was successfully validated with a set of five electron donors which randomly selected from three different groups. Predictive R 2 for the test set was 0.77, indicating good predictive ability of the model. The QSPR model provided the valuable information for the design of better electron donors for propylene polymerization.

Dengue infection is a global burden affecting millions of world population. Previous studies indicated that flavanones were potential dengue virus inhibitors. We discovered that a novel flavanone derivative, 5-hydroxy-7-methoxy-6-methylflavanone (FN5Y), inhibited DENV2 pH-dependent fusion in cell-based system with strong binding efficiency to DENV envelope protein at K (P83, L107, K128, L198), K' (T48, E49, A50, L198, Q200, L277), X' (Y138, V354, I357), and Y' (V97, R99, N103, K246) by molecular dynamic simulation. FN5Y inhibited DENV2 infectivity with EC50s (and selectivity index) of 15.99 ± 5.38 (>6.25), and 12.31 ± 1.64 (2.23) μM in LLC/MK2 and Vero cell lines, respectively, and inhibited DENV4 at 11.70 ± 6.04 (>8.55) μM. CC50s in LLC/MK2, HEK-293, and HepG2 cell lines at 72 h were higher than 100 μM. Time-of-addition study revealed that the maximal efficacy was achieved at early after infection corresponded with pH-dependent fusion. Inactivating the viral particle, interfering with cellular receptors, inhibiting viral protease, or the virus replication complex were not major targets of this compound. FN5Y could become a potent anti-flaviviral drug and can be structurally modified for higher potency using simulation to DENV envelope as a molecular target.

Thioesterase (TE) domain of fatty acid synthase (FAS) is an attractive therapeutic target for design and development of anticancer drugs. In this present work, we search for the potential FAS inhibitors of TE domain from the ZINC database based on similarity search using three natural compounds as templates, including flavonoids, terpenoids, and phenylpropanoids. Molecular docking was used to predict the interaction energy of each screened ligand compared to the reference compound, which is methyl γ-linolenylfluorophosphonate (MGLFP). Based on this computational technique, rosmarinic acid and its eight analogs were observed as a new series of potential FAS inhibitors, which showed a stronger binding affinity than MGLFP. Afterward, nine docked complexes were studied by molecular dynamics simulations for investigating protein–ligand interactions and binding free energies using MM-PB(GB)SA, MM-3DRISM-KH, and QM/MM-GBSA methods. The binding free energy calculation indicated that the ZINC85948835 (R34) displayed the strongest binding efficiency against the TE domain of FAS. There are eight residues (S2308, I2250, E2251, Y2347, Y2351, F2370, L2427, and E2431) mainly contributed for the R34 binding. Moreover, R34 could directly form hydrogen bonds with S2308, which is one of the catalytic triad of TE domain. Therefore, our finding suggested that R34 could be a potential candidate as a novel FAS-TE inhibitor for further drug design.