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Zhou, Y., Li, J., Baryshnikov, G. & Tu, Y. (2022). Unraveling the Abnormal Molecular Mechanism of Suicide Inhibition of Cytochrome P450 3A4. Journal of Chemical Information and Modeling, 62(23), 6172-6181
Open this publication in new window or tab >>Unraveling the Abnormal Molecular Mechanism of Suicide Inhibition of Cytochrome P450 3A4
2022 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 62, no 23, p. 6172-6181Article in journal (Refereed) Published
Abstract [en]

Suicide inhibition of the CYP3A4 enzyme by a drug inactivates the enzyme in the drug biotransformation process and often shows safety concerns about the drug. Despite extensive experimental studies, the abnormal molecular mechanism of a suicide inhibitor that forms a covalent bond with the residue far away from the catalytically active center of CYP3A4 inactivating the enzyme remains elusive. Here, the authors used molecular simulation approaches to study in detail how diquinone methide (DQR), the metabolite product of raloxifene, unbinds from CYP3A4 and inactivates the enzyme at the atomistic level. The results dearly indicate that in one of the intermediate states formed in its unbinding process, DQR covalently binds to Cys239, a residue far away from the catalytically active center of CYP3A4, and hinders the substrate from entering or leaving the enzyme. This work therefore provides an unprecedented way of clarifying the abnormal mechanism of suicide inhibition of the CYP3A4 enzyme.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2022
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-323033 (URN)10.1021/acs.jcim.2c01035 (DOI)000896743100001 ()36457253 (PubMedID)2-s2.0-85143423182 (Scopus ID)
Note

QC 20230112

Available from: 2023-01-12 Created: 2023-01-12 Last updated: 2024-03-18Bibliographically approved
Kuang, G., Murugan, N. A., Zhou, Y., Nordberg, A. & Ågren, H. (2020). Computational Insight into the Binding Profile of the Second-Generation PET Tracer PI2620 with Tau Fibrils. ACS Chemical Neuroscience, 11(6), 900-908
Open this publication in new window or tab >>Computational Insight into the Binding Profile of the Second-Generation PET Tracer PI2620 with Tau Fibrils
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2020 (English)In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 11, no 6, p. 900-908Article in journal (Refereed) Published
Abstract [en]

Abnormal deposition of hyperphosphorylated tau as neurofibrillary tangles (NFTs) is an important pathological hallmark of Alzheimer's disease (AD) and of other neurodegenerative disorders. A noninvasive positron emission tomography (PET) tracer that quantifies neurofibrillary tangles in vivo can enhance the clinical diagnosis of AD and can also be used to evaluate the efficacy of therapeutics aimed at reducing the abnormal aggregation of the tau fibril in the brain. In this paper, we study the binding profile of fibrillar tau aggregates with a PET tracer PI2620, which is a new second generation tau PET tracer that is presently experimentally and clinically studied. The target structure for the tau fibril is based on cryo-electron microscopy (cryo-EM) structure. A multiscale simulation workflow including molecular docking, molecular dynamics simulation, metadynamics simulation, and free energy calculations was implemented. We find that PI2620 can bind to eight surface binding sites, three core binding sites, and one entry site. The binding at the core sites and entry site is found to be much more favorable than that on the surface sites due to stronger hydrophobic interactions and less solvent exposure. Furthermore, the entry site which is formed by the terminal beta-sheets of the fibril is found to have the highest binding affinity to PI2620. Importantly, the binding capacity at the entry site can be much higher than that at other core sites, due to its easy accessibility. Therefore, the entry site is believed to be the major binding site for PI2620. A previous computational study on tracers with tau fibrils reports a maximum of four binding sites. Through use of methods that allow us to locate "cryptic binding sites", we report here additional core sites available for binding and we address the limitation of using the cryo-EM structure alone for structure-based tracer design. Our results could be helpful for elucidating the binding mechanism of imaging tracers with the fibrillar form of tau, a knowledge that in turn can be used to guide the development of compounds with higher affinity and selectivity for tau using structure-based design strategies.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020
Keywords
Tau, PET tracer, PI2620, molecular docking, molecular dynamics, metadynamics
National Category
Clinical Medicine
Identifiers
urn:nbn:se:kth:diva-272926 (URN)10.1021/acschemneuro.9b00578 (DOI)000526391700008 ()32069017 (PubMedID)2-s2.0-85082094037 (Scopus ID)
Note

QC 20200525

Available from: 2020-05-25 Created: 2020-05-25 Last updated: 2024-03-18Bibliographically approved
Zeng, S., Dou, W., Li, M., Zhou, Y., Guo, J., Zhao, N., . . . Xie, H. (2020). Discovery of an Orally Active and Long-Acting DPP-IV Inhibitor through Property-Based Optimization with an in Silico Biotransformation Prediction Tool. ChemMedChem, 15(16), 1608-1617
Open this publication in new window or tab >>Discovery of an Orally Active and Long-Acting DPP-IV Inhibitor through Property-Based Optimization with an in Silico Biotransformation Prediction Tool
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2020 (English)In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 15, no 16, p. 1608-1617Article in journal (Refereed) Published
Abstract [en]

Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising molecules for interventions for type 2 diabetes. Once weekly dosing brings greater patient compliance and more stable glycemic control. Starting from our previous highly potent compound with a thienoprimidine scaffold, which is unfortunately severely hit by hepatic biotransformation, a lead compound was rapidly generated by drawing on the experience of our previously discovered long-acting compounds with pyrrolopyrimidine scaffold. With the aid of an in silico biotransformation prediction tool, (R)-2-((2-(3-aminopiperidin-1-yl)-4-oxo-6-(pyridin-3-yl)thieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-fluorobenzonitrile was eventually generated and determined to have high potency, a fine pharmacokinetic profile, and a long-acting in vivo efficacy.

Place, publisher, year, edition, pages
John Wiley and Sons Ltd, 2020
Keywords
biostability, DPP-IV, in silico testing, inhibitors, metabolism, 2 [[2 (3 aminopiperidin 1 yl) 4 oxo 6 (1h pyrazol 4 yl)thieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 4 oxo 6 (pyridin 3 yl)thieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 4 oxo 6 (pyridin 4 yl)thieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 4 oxo 6 [3 (trifluoromethyl)phenyl]thieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 4 oxo 7 (pyridin 3 yl)thieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 4 oxothieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 6 (2 methoxypyridin 4 yl) 4 oxothieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 6 (2 methylpyridin 4 yl) 4 oxothieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 6 (3 fluorophenyl) 4 oxothieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 6 (3, 5 dimethylisoxazol 4 yl) 4 oxothieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 6 (4 fluorophenyl) 4 oxothieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 6 bromo 4 oxothieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 6 [3 (methylsulfonyl)phenyl] 4 oxothieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 7 bromo 4 oxothieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 7 fluoro 4 oxothieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 7 methyl 4 oxo 6 (pyridin 3 yl)thieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, 2 [[2 (3 aminopiperidin 1 yl) 7 methyl 4 oxothieno[3, 2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile, antidiabetic agent, cytochrome P450, dipeptidyl peptidase IV inhibitor, long acting drug, pyrimidine derivative, trelagliptin, unclassified drug, xanthine derivative, animal experiment, area under the curve, Article, computer model, controlled study, drug bioavailability, drug design, drug efficacy, drug half life, drug potency, drug transformation, glycemic control, IC50, in vitro study, in vivo study, infant, male, maximum plasma concentration, mean residence time, metabolic stability, nonhuman, priority journal, rat, time to maximum plasma concentration
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-286487 (URN)10.1002/cmdc.202000175 (DOI)000545786500001 ()32558296 (PubMedID)2-s2.0-85087292104 (Scopus ID)
Note

QC 20201217

Available from: 2020-12-17 Created: 2020-12-17 Last updated: 2022-06-25Bibliographically approved
Li, J., Zhou, Y., Tang, Y., Li, W. & Tu, Y. (2020). Dissecting the Structural Plasticity and Dynamics of Cytochrome P450 2B4 by Molecular Dynamics Simulations. Journal of Chemical Information and Modeling, 60(10), 5026-5035
Open this publication in new window or tab >>Dissecting the Structural Plasticity and Dynamics of Cytochrome P450 2B4 by Molecular Dynamics Simulations
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2020 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 60, no 10, p. 5026-5035Article in journal (Refereed) Published
Abstract [en]

The plasticity of cytochromes P450 (P450s) is known to contribute significantly to their catalytic capacity of metabolizing various substrates. Although numerous studies have been performed, factors governing the plasticity and dynamics of P450s are still not fully understood. In this study, taking CYP2B4 as an example, we dissect the protein plasticity and dynamics in different environments. CYP2B4 is featured by a high degree of plasticity, which exhibits open, closed, and intermediate states. By analyzing the CYP2B4 crystal structures, we identified the structural features for the closed, open, and intermediate states. Interestingly, formation of the dimer structure was found in the open and intermediate states. The subsequent molecular dynamics (MD) simulations of the open structure in water confirmed the importance of the dimer form in stabilizing the open conformations. MD simulations of the closed and open structures in the membrane environment and the free energies for opening the F-G cassette obtained from the umbrella sampling calculations indicate that the membrane environment is important for stabilizing the F-G cassette. The dynamical network analysis indicates that Asp105 on the B-C loop plays an important role in transiting the structure from the open to the intermediate state. Our results thus unveil the mechanisms of dimer formation and open-to-intermediate transition for CYP2B4 in the water and membrane environments.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-288639 (URN)10.1021/acs.jcim.0c00482 (DOI)000586716900055 ()32808774 (PubMedID)2-s2.0-85094683974 (Scopus ID)
Note

QC 20210112

Available from: 2021-01-12 Created: 2021-01-12 Last updated: 2022-06-25Bibliographically approved
Zou, R., Zhou, Y., Wang, Y., Guanglin, K., Ågren, H., Wu, J. & Tu, Y. (2020). Free Energy Profile and Kinetics of Coupled Folding and Binding of the Intrinsically Disordered Protein p53 with MDM2. Journal of Chemical Information and Modeling, 60(3), 1551-1558
Open this publication in new window or tab >>Free Energy Profile and Kinetics of Coupled Folding and Binding of the Intrinsically Disordered Protein p53 with MDM2
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2020 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 60, no 3, p. 1551-1558Article in journal (Refereed) Published
Abstract [en]

Intrinsically disordered proteins (IDPs) exert their functions by binding to partner proteins via a complex process that includes coupled folding and binding. Because inhibiting the binding of the IDP p53 to its partner MDM2 has become a promising strategy for the design of anticancer drugs, we carried out metadynamics simulations to study the coupled folding and binding process linking the IDP p53 to MDM2 in atomic detail. Using bias-exchange metadynamics (BE-MetaD) and infrequent metadynamics (InMetaD), we estimated the binding free energy, the unbinding rate, and the binding rate. By analyzing the stable intermediates, we uncovered the role non-native interactions played in the p53-MDM2 binding/unbinding process. We used a three-state model to describe the whole binding/unbinding process and to obtain the corresponding rate constants. Our work shows that the binding of p53 favors an induced-fit mechanism which proceeds in a stepwise fashion. Our results can be helpful for gaining an in-depth understanding of the coupled folding and binding process needed for the design of MDM2 inhibitors.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-272941 (URN)10.1021/acs.jcim.9b00920 (DOI)000526390800044 ()32053358 (PubMedID)2-s2.0-85082147510 (Scopus ID)
Note

QC 20200520

Available from: 2020-05-20 Created: 2020-05-20 Last updated: 2022-06-26Bibliographically approved
Zhou, Y. (2020). Modeling Kinetics of Protein-Ligand Systems. (Doctoral dissertation). KTH Royal Institute of Technology
Open this publication in new window or tab >>Modeling Kinetics of Protein-Ligand Systems
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Protein-ligand interactions dominate many life activities and are crucial for thedevelopment of tracers for diagnosing diseases and drugs for treating diseases.For protein-ligand interactions, the binding affinity is conventionally believedto be the most important indicator. However, there is increasing evidencethat the binding affinity alone is not sufficient for providing comprehensiveinformation about protein-ligand interactions. Kinetics, which describes theduration of the interactions and is closely related to the interaction mechanism,is considered as important as, or even more important than, the binding affinityin the study of the mechanisms of protein-ligand interactions.Although kinetics parameters of a protein-ligand system can be measuredexperimentally, the underlying molecular mechanism for the kinetics is difficultto reveal by experiment, which is, however, essential for understanding theorigin of the kinetics and for the rational design of drugs or tracers. In the lastdecade, computer simulations have emerged as a powerful tool for studying biomolecularsystems. Computer simulation methods have also been developedfor modeling kinetics of protein-ligand systems.In this thesis, I explored computer simulations for modeling kinetics propertiesof four different protein-ligand systems. In paper I, I studied the relationshipbetween the ligand binding and conformational changes of the ATAD2-BRD protein. In paper II, I investigated the free energy profile for the coupledfolding and binding of the intrinsically disordered protein p53 with MDM2and calculated the rate constants for the binding and unbinding processes. Inpaper III, I revealed the unbinding paths of the PET tracer ASEM from the  a7-nAChR, calculated the unbinding rate, and explored a way of how to findthe key protein conformational changes strongly coupled to the ligand unbindingprocess. In paper IV, I further refined our methodology for finding theunbinding paths and clarified the unbinding mechanism of the metabolite ofraloxifene from the enzyme CYP3A4.

Abstract [sv]

Protein-ligandinteraktioner dominerar många livsaktiviteter och är avgörande för utvecklingen av spårare för att diagnostisera sjukdomar och läkemedel för behandling av sjukdomar. För protein-ligandinteraktioner antas konventionell bindningsaffinitet vara den viktigaste indikatorn. Det finns emellertid ökande bevis på att bindningsaffiniteten enbart inte är tillräcklig för att tillhandahålla omfattande information om protein-ligandinteraktioner. Kinetik, som beskriver varaktigheten på interaktioner och är nära besläktad med interaktionsmekanismen, anses vara så viktig som, eller ännu viktigare än bindningsaffiniteten i studien av mekanismerna för protein-ligandinteraktioner.

 

Även om kinetikparametrar i ett protein-ligandsystem kan mätas experimentellt är den underliggande molekylära mekanismen för kinetiken svår att avslöja genom experiment, vilket dock är väsentligt för att förstå kinetikens ursprung och för den rationella utformningen av läkemedel eller spårare . Under det senaste decenniet har datorsimuleringar framkommit som ett kraftfullt verktyg för att studera biomolekylära system. Datorsimuleringsmetoder har också utvecklats för att modellera kinetik för protein-ligandsystem.

 

I den här avhandlingen undersökte jag datorsimuleringar för modellering av kinetiska egenskaper hos fyra olika protein-ligandsystem. I papper I studerade jag sambandet mellan ligandbindningen och konformationella förändringar av ATAD2-BRD-proteinet. I papper II undersökte jag den fria energiprofilen för den kopplade vikningen och bindningen av det intrinsiskt störda proteinet p53-peptid med MDM2 och beräknade hastighetskonstanterna för bindnings- och bindningsförfarandena. I papper III avslöjade jag de bindande vägarna för PET-spåraren ASEM från α7-nAChR, beräknade bindningsgraden och utforskade ett sätt att hitta de viktiga proteinkonformationella förändringarna starkt kopplade till ligandbindningsprocessen. I papper IV förfinade jag ytterligare vår metod för att hitta de bindande vägarna och klargjorde den bindande mekanismen för metaboliten av raloxifen från enzymet CYP3A4.

Place, publisher, year, edition, pages
KTH Royal Institute of Technology, 2020. p. 57
Series
TRITA-CBH-FOU ; 2020:25
National Category
Theoretical Chemistry
Research subject
Theoretical Chemistry and Biology
Identifiers
urn:nbn:se:kth:diva-273146 (URN)978-91-7873-545-7 (ISBN)
Public defence
2020-06-03, https://kth-se.zoom.us/webinar/register/WN_ZxwH8-GQTFaTv9ifiiTsAA ​, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 2020-05-08

Available from: 2020-05-08 Created: 2020-05-07 Last updated: 2022-06-26Bibliographically approved
Zhou, Y., Zou, R., Guanglin, K., Angstrom, B., Halidin, C., Ågren, H. & Tu, Y. (2019). Enhanced Sampling Simulations of Ligand Unbinding Kinetics Controlled by Protein Conformational Changes. Journal of Chemical Information and Modeling, 59(9), 3910-3918
Open this publication in new window or tab >>Enhanced Sampling Simulations of Ligand Unbinding Kinetics Controlled by Protein Conformational Changes
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2019 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 59, no 9, p. 3910-3918Article in journal (Refereed) Published
Abstract [en]

Understanding unbinding kinetics of protein-ligand systems is of great importance for the design of ligands with desired specificity and safety. In recent years, enhanced sampling techniques have emerged as effective tools for studying unbinding kinetics of protein-ligand systems at the atomistic level. However, in many protein-ligand systems, the ligand unbinding processes are strongly coupled to protein conformational changes and the disclosure of the hidden degrees of freedom closely related to the protein conformational changes so that sampling is enhanced over these degrees of freedom remains a great challenge. Here, we show how potential-scaled molecular dynamics (sMD) and infrequent metadynamics (InMetaD) simulation techniques can be combined to successfully reveal the unbinding mechanism of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[F-18]fluorodibenzo[b,d]thiophen e 5,5-dioxide ([F-18]ASEM) from a chimera structure of the alpha 7-nicotinic acetylcholine receptor. By using sMD simulations, we disclosed that the "close to "open" conformational change of loop C plays a key role in the ASEM unbinding process. By carrying out InMetaD simulations with this conformational change taken into account as an additional collective variable, we further captured the key states in the unbinding process and clarified the unbinding mechanism of ASEM from the protein. Our work indicates that combining sMD and InMetaD simulation techniques can be an effective approach for revealing the unbinding mechanism of a protein-ligand system where protein conformational changes control the unbinding process.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2019
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-262805 (URN)10.1021/acs.jcim.9b00523 (DOI)000487769800034 ()31454236 (PubMedID)2-s2.0-85072587758 (Scopus ID)
Note

QC 20191021

Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2022-06-26Bibliographically approved
Makafe, G. G., Hussain, M., Surineni, G., Tan, Y., Wong, N.-K., Julius, M., . . . Zhang, T. (2019). Quinoline Derivatives Kill Mycobacterium tuberculosis by Activating Glutamate Kinase. Cell Chemical Biology, 26(8), 1187-+
Open this publication in new window or tab >>Quinoline Derivatives Kill Mycobacterium tuberculosis by Activating Glutamate Kinase
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2019 (English)In: Cell Chemical Biology, ISSN 2451-9456, E-ISSN 2451-9448, Vol. 26, no 8, p. 1187-+Article in journal (Refereed) Published
Abstract [en]

There is a great need for identification and development of new anti-tuberculosis drugs with novel targets. Recent drug-discovery efforts typically focus on identifying inhibitors but not activators that perturb metabolic enzymes' functions as a means to kill Mycobacterium tuberculosis (Mtb). Here, we describe a class of quinoline compounds, Z0933/Z0930, which kill Mtb by acting as activators of glutamate kinase (GK), a previously untargeted enzyme catalyzing the first step of proline biosynthesis. We further show that Z0933/Z0930 augment proline production and induce Mtb killing via proline-derived redox imbalance and production of reactive oxygen species. This work highlights the effectiveness of gain-of-function probes against Mtb and provides a framework for the discovery of next-generation allosteric activators of GK.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-257805 (URN)10.1016/j.chembiol.2019.05.003 (DOI)000481604100015 ()31204286 (PubMedID)2-s2.0-85070354857 (Scopus ID)
Note

QC 20190912

Available from: 2019-09-12 Created: 2019-09-12 Last updated: 2022-06-26Bibliographically approved
Zhou, H., Zhou, Y., Xu, J., Liu, L., Ma, J., Zhang, W., . . . Li, K. (2019). Tannic Acid-A Universal Immobilization and Fixation Agent for Nanocarbon Materials: A Novel Strategy for Aqueous Fabrication of Functional Nanocarbon Coating onto Silicon-Based Substances. ACS Sustainable Chemistry and Engineering, 7(22), 18534-18541
Open this publication in new window or tab >>Tannic Acid-A Universal Immobilization and Fixation Agent for Nanocarbon Materials: A Novel Strategy for Aqueous Fabrication of Functional Nanocarbon Coating onto Silicon-Based Substances
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2019 (English)In: ACS Sustainable Chemistry and Engineering, E-ISSN 2168-0485, Vol. 7, no 22, p. 18534-18541Article in journal (Refereed) Published
Abstract [en]

We report a feasible and universal approach to fabricate nanocarbon material (NCM) coatings onto a wide range of silicon-based substances. Benefitting from the phenolic hydroxyl and star-shaped branched molecular structure, tannic acid (TA) could act as a functional agent for immobilization and fixation of NCMs in the aqueous phase. More specifically, steered molecular dynamics simulations verified that some unionized chains of TA could tightly attach to the NCMs surface in the neutral aqueous environment by pi-pi stacking interactions, and other free arms with ionized phenolic hydroxyl could act as surface charges of the TA/NCM coacervates, resulting in enhanced colloidal stability of this dispersion. Subsequently, these free arms could also interact with the aminated silicon-based substances, enabling TA to act as a "bridge" between the NCM and the silicon-based substances to form the nanocarbon coating. The obtained polydimethylsiloxane with TA/NCM coating represents favorable electrical and thermal conductivity along with excellent electromechanical performance under the cyclic compression-release test. This strategy is a great improvement for the fabrication of NCM layers and devices, which is not necessary to make the hydrophilic modification of NCM and beneficial to enhance the interaction between the carbon layer and substrate, avoiding the coating separation from the substances.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
Keywords
tannic acid, nanocarbon materials, bridge molecule, coating, silicon-based materials
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-265478 (URN)10.1021/acssuschemeng.9b04623 (DOI)000498289300036 ()2-s2.0-85074322236 (Scopus ID)
Note

QC 20191218

Available from: 2019-12-18 Created: 2019-12-18 Last updated: 2022-06-26Bibliographically approved
Ti, H., Zhou, Y., Liang, X., Li, R., Ding, K. & Zhao, X. (2019). Targeted Treatments for Chronic Obstructive Pulmonary Disease (COPD) Using Low-Molecular-Weight Drugs (LMWDs). Journal of Medicinal Chemistry, 62(13), 5944-5978
Open this publication in new window or tab >>Targeted Treatments for Chronic Obstructive Pulmonary Disease (COPD) Using Low-Molecular-Weight Drugs (LMWDs)
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2019 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 62, no 13, p. 5944-5978Article in journal (Refereed) Published
Abstract [en]

Chronic obstructive pulmonary disease (COPD) is a very common and frequently fatal airway disease. Current therapies for COPD depend mainly on long-acting bronchodilators, which cannot target the pathogenic mechanisms of chronic inflammation in COPD. New pharmaceutical therapies for the inflammatory processes of COPD are urgently needed. Several anti-inflammatory targets have been identified based on increased understanding of the pathogenesis of COPD, which raises new hopes for targeted treatment of this fatal respiratory disease. In this review, we discuss the recent advances in bioactive low-molecular-weight drugs (LMWDs) for the treatment of COPD and, in addition to the first-line drug bronchodilators, focus particularly on low-molecular-weight anti-inflammatory agents, including modulators of inflammatory mediators, inflammasome inhibitors, protease inhibitors, antioxidants, PDE4 inhibitors, kinase inhibitors, and other agents. We also provide new insights into targeted COPD treatments using LMWDs, particularly small-molecule agents.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:kth:diva-255564 (URN)10.1021/acs.jmedchem.8b01520 (DOI)000475543300002 ()30682248 (PubMedID)2-s2.0-85061898645 (Scopus ID)
Note

QC 20190802

Available from: 2019-08-02 Created: 2019-08-02 Last updated: 2024-03-18Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-4167-6413

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