kth.sePublications
Change search
Link to record
Permanent link

Direct link
Publications (10 of 20) Show all publications
Zhou, Y., Guanglin, K., Li, J., Halldin, C., Nordberg, A., Langstrom, B., . . . Agren, H. (2021). In silico studies of ASEM analogues targeting alpha 7-nAChR and experimental verification. RSC Advances, 11(7), 3942-3951
Open this publication in new window or tab >>In silico studies of ASEM analogues targeting alpha 7-nAChR and experimental verification
Show others...
2021 (English)In: RSC Advances, E-ISSN 2046-2069, Vol. 11, no 7, p. 3942-3951Article in journal (Refereed) Published
Abstract [en]

The alpha 7 nicotinic acetylcholine receptor (alpha 7-nAChR) is implicated in a variety of neurodegenerative and neuropsychiatric disorders, such as Alzheimer's disease (AD) and schizophrenia. The progress of these disorders can be studied using positron emission tomography (PET) with radiotracers for alpha 7-nAChR. [F-18]ASEM and [F-18] para-ASEM (also referred to as [F-18]DBT-10) are novel and potent alpha 7-nAChR PET radiotracers which have successfully been used in human subjects and nonhuman primates, though further improvement of them is still a pressing task in the community of neurodegeneration research. In this work, we demonstrate the use of modern in silico techniques to predict the binding modes, binding strengths, and residence times for molecular PET tracers binding to proteins, using ASEM and DBT-10 as a showcase of the predictive and interpretational power of such techniques, in particular free energy perturbation theory. The corresponding compounds were synthesized and further tested by in vitro binding experiment for validation. Encouragingly, our in silico modeling can correctly predict the binding affinities of the ASEM analogues. The structure-activity relationships for the ortho- and para-substitutions are well explained at the atomistic level and provide structure-based guiding for the future development of PET tracers for alpha 7-nAChR. A discussion is presented on the complementary use of in silico rational methods based on atomic and electronic principles for in vitro characterization of PET tracers.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2021
National Category
Neurosciences
Identifiers
urn:nbn:se:kth:diva-291942 (URN)10.1039/d0ra10435c (DOI)000615282100018 ()35747361 (PubMedID)2-s2.0-85099926024 (Scopus ID)
Note

QC 20210324

Available from: 2021-03-24 Created: 2021-03-24 Last updated: 2022-09-23Bibliographically 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
Show others...
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
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
Show others...
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
Nag, S., Jia, Z., Datta, P., Azpiazu, P. M., Arakawa, R., Varnas, K., . . . Halldin, C. (2019). Development of novel C-11- labeled ASEM analogs for detection of neuronal nicotinic acetylcholine receptors (alpha 7-nAChR). Paper presented at 32nd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 12-16, 2019, Barcelona, SPAIN. European Journal of Nuclear Medicine and Molecular Imaging, 46(SUPPL 1), S228-S228
Open this publication in new window or tab >>Development of novel C-11- labeled ASEM analogs for detection of neuronal nicotinic acetylcholine receptors (alpha 7-nAChR)
Show others...
2019 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no SUPPL 1, p. S228-S228Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
SPRINGER, 2019
National Category
Basic Medicine
Identifiers
urn:nbn:se:kth:diva-264304 (URN)000492444402031 ()
Conference
32nd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 12-16, 2019, Barcelona, SPAIN
Note

QC 20191203

Available from: 2019-12-03 Created: 2019-12-03 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
Show others...
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
Zou, R., Guanglin, K., Ågren, H., Nordberg, A., Långström, B. & Tu, Y. (2019). Free Energy Profile for Penetration of Pittsburgh Compound-B into the Amyloid beta Fibril. ACS Chemical Neuroscience, 10(3), 1783-1790
Open this publication in new window or tab >>Free Energy Profile for Penetration of Pittsburgh Compound-B into the Amyloid beta Fibril
Show others...
2019 (English)In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 10, no 3, p. 1783-1790Article in journal (Refereed) Published
Abstract [en]

The amyloid beta (A beta) fibril is a hallmark of Alzheimer's disease (AD) and has therefore served as an important target for early diagnosis of AD. The Pittsburgh Compound-B (PiB) is one of the most famous positron emission tomography (PET) tracers commonly used for in vivo detection of A beta fibrils. Many theoretical studies have predicted the existence of various core binding sites with different microenvironments for probes binding to the A beta fibril. However, little attention has been devoted to how the probes actually penetrate into the different core binding sites. In this study, an integrated molecular modeling scheme is used to study the penetration of PiB into the core binding sites of the A beta(1-42) fibril structure recently obtained by cryogenic electron microscopy. We find that there are two core binding sites for PiB with dramatic differences in cavity size and microenvironment properties, and furthermore that the penetration of PiB into site-1 is energetically prohibitive, whereas the penetration into site 2 is much more favorable. Therefore, the binding capacity at site-2 may be larger than that at site-1 despite its lower binding affinity. Our results thus suggest that site-2 may be a major binding site for PiB binding to A beta fibril and emphasize the importance to adopt a full dynamical picture when studying tracer fibril binding problems in general, something that in turn can be used to guide the development of tracers with higher affinity and selectivity for the A beta fibril.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
Keywords
Amyloid beta fibril, binding sites, imaging agents, free energy profiles, molecular dynamics simulation, umbrella sampling
National Category
Neurosciences
Identifiers
urn:nbn:se:kth:diva-249893 (URN)10.1021/acschemneuro.8b00662 (DOI)000462259900081 ()30698013 (PubMedID)2-s2.0-85061903405 (Scopus ID)
Note

QC 20190424

Available from: 2019-04-24 Created: 2019-04-24 Last updated: 2023-08-28Bibliographically approved
Guanglin, K., Murugan, N. A. & Ågren, H. (2019). Mechanistic Insight into the Binding Profile of DCVJ and alpha-Synuclein Fibril Revealed by Multiscale Simulations. ACS Chemical Neuroscience, 10(1), 610-617
Open this publication in new window or tab >>Mechanistic Insight into the Binding Profile of DCVJ and alpha-Synuclein Fibril Revealed by Multiscale Simulations
2019 (English)In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 10, no 1, p. 610-617Article in journal (Refereed) Published
Abstract [en]

Parkinson's disease (PD) is a serious neuro-degenerative disease and is characterized by abnormal alpha-synuclein (alpha-syn) accumulation in Lewy bodies (LB) and 2 Lewy neurites (LN), which makes alpha-syn an important imaging target for PD. An imaging probe that quantifies fibrillar alpha-syn can enhance the clinical diagnosis of PD and can also be used to evaluate the efficacy of therapeutics aimed at reducing the abnormal aggregation of the alpha-syn fibril in the brain. In this paper, we study the binding profile of fibrillar alpha-syn with a fluorescent probe 4-(dicyanovinyl)julolidine (DCVJ), which is being explored for identifying alpha-syn imaging agents. A multiscale simulation workflow including molecular docking, molecular dynamics, metadynamics, and QM/MM calculations was implemented. We find that DCVJ can bind to multiple sites of alpha-syn which are located either at the surface or in the core. Free energy calculations using implicit solvent models reveal that the most favorable binding mode for DCVJ is associated with the core binding site and is further confirmed by metadyamics simulation. Besides, a dynamic binding pathway is discovered, which reveals that DCVJ binds gradually into the core of the fibril passing through several intermediate states. The conformational arrest of the dicyano vinyl group in the fibrillar environment could explain the reason behind the fibril-specific fluorescence of DCVJ. Furthermore, based on hybrid QM/MM calculations, the molecular geometry of the dicyano vinyl group is found to be environment specific which explains why DCVJ serves as a staining agent for such fibrillar-like environments. Our results could be helpful for elucidating the binding mechanism of imaging tracers with the fibrillar form of alpha-syn and explain their fibrillar-specific optical properties, a knowledge that in turn can be used to guide the design and development of compounds with higher affinity and selectivity for alpha-syn using structure-based strategies.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2019
Keywords
alpha-Synuclein, DCVJ, imaging agents, molecular docking, binding free energy calculations, metadynamics
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-243968 (URN)10.1021/acschemneuro.8b00465 (DOI)000456351300062 ()30277753 (PubMedID)2-s2.0-85055257565 (Scopus ID)
Note

QC 20190301

Available from: 2019-03-01 Created: 2019-03-01 Last updated: 2023-08-28Bibliographically approved
Zhou, Y., Hussain, M., Guanglin, K., Zhang, J. & Tu, Y. (2018). Mechanistic insights into peptide and ligand binding of the ATAD2-bromodomain via atomistic simulations disclosing a role of induced fit and conformational selection. Physical Chemistry, Chemical Physics - PCCP, 20(36), 23222-23232
Open this publication in new window or tab >>Mechanistic insights into peptide and ligand binding of the ATAD2-bromodomain via atomistic simulations disclosing a role of induced fit and conformational selection
Show others...
2018 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 20, no 36, p. 23222-23232Article in journal (Refereed) Published
Abstract [en]

ATAD2 has emerged as a promising bromodomain (BRD)-containing therapeutic drug target in multiple human cancers. However, recent druggability assessment studies predicted ATAD2's BRD as a target 'difficult to drug' because its binding pocket possesses structural features that are unfeasible for ligand binding. Here, by using all-atom molecular dynamics simulations and an advanced metadynamics method, we demonstrate a dynamic view of the binding pocket features which can hardly be obtained from the "static" crystal data. The most important features disclosed from our simulation data, include: (1) a distinct 'open-to-closed' conformational switch of the ZA loop region in the context of peptide or ligand binding, akin to the induced fit mechanism of molecular recognition, (2) a dynamic equilibrium of the BC loop "in" and "out" conformations, highlighting a role in the conformational selection mechanism for ligand binding, and (3) a new binding region identified distal to the histone-binding pocket that might have implications in bromodomain biology and in inhibitor development. Moreover, based on our simulation results, we propose a model for an "auto-regulatory" mechanism of ATAD2's BRD for histone binding. Overall, the results of this study will not only have implications in bromodomain biology but also provide a theoretical basis for the discovery of new ATAD2's BRD inhibitors.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2018
Keywords
AAA protein, ATAD2 protein, human, DNA binding protein, ligand, peptide, binding site, chemistry, conformation, human, molecular dynamics, ATPases Associated with Diverse Cellular Activities, Binding Sites, DNA-Binding Proteins, Humans, Ligands, Molecular Conformation, Molecular Dynamics Simulation, Peptides
National Category
Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:kth:diva-236425 (URN)10.1039/c8cp03860k (DOI)000447370600005 ()30137066 (PubMedID)2-s2.0-85053795262 (Scopus ID)
Note

QC 20181026

Available from: 2018-10-26 Created: 2018-10-26 Last updated: 2022-06-26Bibliographically approved
Kuang, G., Zhou, Y., Zou, R., Halldin, C., Nordberg, A., Långström, B., . . . Tu, Y. (2017). Characterization of the binding mode of the PET tracer [18F]ASEM to a chimera structure of the α7 nicotinic acetylcholine receptor. RSC Advances, 7(32), 19787-19793
Open this publication in new window or tab >>Characterization of the binding mode of the PET tracer [18F]ASEM to a chimera structure of the α7 nicotinic acetylcholine receptor
Show others...
2017 (English)In: RSC Advances, E-ISSN 2046-2069, Vol. 7, no 32, p. 19787-19793Article in journal (Refereed) Published
Abstract [en]

The α7 nicotinic acetylcholine receptor (α7-nAChR) is assumed to be implicated in a variety of neurological disorders, such as schizophrenia and Alzheimer's disease (AD). The progress of these disorders can be studied through imaging α7-nAChR with positron emission tomography (PET). [18F]ASEM is a novel and potent α7-nAChR PET radioligand showing great promise in recent tests. However, the mechanism of the molecular interaction between [18F]ASEM and α7-nAChR is still unclear. In this paper, the binding profile of [18F]ASEM to a chimera structure of α7-nAChR was investigated with molecular docking, molecular dynamics, and metadynamics simulation methods. We found that [18F]ASEM binds at the same site as the crystallized agonist epibatidine but with a different binding mode. The dibenzo[b,d]thiophene ring has a different orientation compared to the pyridine ring of epibatidine and has van der Waals interactions with residues from loop C on one side and π-π stacking interaction with Trp53 on the other side. The conformation of Trp53 was found to have a great impact on the binding of [18F]ASEM. Six binding modes in terms of the side chain dihedral angles χ1 and χ2 of Trp53 were discovered by metadynamics simulation. In the most stable binding mode, Trp53 adopts a different conformation from that in the crystalline structure and has a rather favorable π-π stacking interaction with [18F]ASEM. We believe that these discoveries can be valuable for the development of novel PET radioligands.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2017
Keywords
Binding energy, Dihedral angle, Molecular dynamics, Neurodegenerative diseases, Positron emission tomography, Van der Waals forces, Alzheimer's disease, Crystalline structure, Metadynamics simulations, Molecular docking, Neurological disorders, Nicotinic acetylcholine receptors, Positron emission tomography (PET), Van Der Waals interactions, Bins
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-207402 (URN)10.1039/c7ra00496f (DOI)000399242100041 ()2-s2.0-85017176981 (Scopus ID)
Funder
Swedish Foundation for Strategic Research , RB13-0192Stockholm County Council, K1764-2013Swedish National Infrastructure for Computing (SNIC), m.2015-1-396
Note

QC 20170601

Available from: 2017-06-01 Created: 2017-06-01 Last updated: 2024-03-18Bibliographically approved
Rajasekhar, K., Narayanaswamy, N., Natarajan, A. M., Kuang, G., Ågren, H. & Govindaraju, T. (2016). A High Affinity Red Fluorescence and Colorimetric Probe for Amyloid beta Aggregates. Scientific Reports, 6, Article ID 23668.
Open this publication in new window or tab >>A High Affinity Red Fluorescence and Colorimetric Probe for Amyloid beta Aggregates
Show others...
2016 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 6, article id 23668Article in journal (Refereed) Published
Abstract [en]

A major challenge in the Alzheimer's disease (AD) is its timely diagnosis. Amyloid beta (A beta) aggregates have been proposed as the most viable biomarker for the diagnosis of AD. Here, we demonstrate hemicyanine-based benzothiazole-coumarin (TC) as a potential probe for the detection of highly toxic A beta(42) aggregates through switch-on, enhanced (similar to 30 fold) red fluorescence (E-max = 654 nm) and characteristic colorimetric (light red to purple) optical outputs. Interestingly, TC exhibits selectivity towards A beta(42) fibrils compared to other abnormal protein aggregates. TC probe show nanomolar binding affinity (K-alpha = 1.72 x 10(7) M-1) towards A beta(42) aggregates and also displace ThT bound to A beta(42) fibrils due to its high binding affinity. The A beta(42) fibril-specific red-shift in the absorption spectra of TC responsible for the observed colorimetric optical output has been attributed to micro-environment change around the probe from hydrophilic-like to hydrophobic-like nature. The binding site, binding energy and changes in optical properties observed for TC upon interaction with A beta(42) fibrils have been further validated by molecular docking and time dependent density functional theory studies.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-185620 (URN)10.1038/srep23668 (DOI)000373324000001 ()27032526 (PubMedID)2-s2.0-84963699553 (Scopus ID)
Note

QC 20160429

Available from: 2016-04-29 Created: 2016-04-25 Last updated: 2024-03-18Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3138-820X

Search in DiVA

Show all publications