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Summer holiday approaches and at MedTrace Pharma A/S we have celebrated some of the impressive achievements we’ve reached this first half year of…
Summer holiday approaches and at MedTrace Pharma A/S we have celebrated some of the impressive achievements we’ve reached this first half year of…
Ann-Beth Nørholm synes godt om dette
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Looking to make a difference in the lives of patients with #ipf? Come join our dynamic team at Vicore and be a part of this exciting new stage of…
Looking to make a difference in the lives of patients with #ipf? Come join our dynamic team at Vicore and be a part of this exciting new stage of…
Ann-Beth Nørholm synes godt om dette
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Big news today! I am happy to share that Pricia has acquired the Pricing360 software platform, and rebranded it to Atlas360. This acquisition is a…
Big news today! I am happy to share that Pricia has acquired the Pricing360 software platform, and rebranded it to Atlas360. This acquisition is a…
Ann-Beth Nørholm synes godt om dette
Erfaring og uddannelse
Licenser og certificeringer
Erfaring med frivilligt arbejde
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Bestyrelsesformand
Ledøje-Smørum Tennisklub
– nu 2 år 4 måneder
Udgivelser
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Thermodynamic Characterization of New Positive Allosteric Modulators Binding to the Glutamate Receptor A2 Ligand-Binding Domain: Combining Experimental and Computational Methods Unravels Differences in Driving Forces
J. Chem. Inf. Model. (2014) 54(12): 3404-16.
Positive allosteric modulation of the ionotropic glutamate receptor GluA2 presents a potential treatment of cognitive disorders, for example, Alzheimer's disease. In the present study, we describe the synthesis, pharmacology, and thermodynamic studies of a series of monofluoro-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. Measurements of ligand binding by isothermal titration calorimetry (ITC) showed similar binding affinities for the modulator series at the GluA2 LBD but…
Positive allosteric modulation of the ionotropic glutamate receptor GluA2 presents a potential treatment of cognitive disorders, for example, Alzheimer's disease. In the present study, we describe the synthesis, pharmacology, and thermodynamic studies of a series of monofluoro-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. Measurements of ligand binding by isothermal titration calorimetry (ITC) showed similar binding affinities for the modulator series at the GluA2 LBD but differences in the thermodynamic driving forces. Binding of 5c (7-F) and 6 (no-F) is enthalpy driven, and 5a (5-F) and 5b (6-F) are entropy driven. For 5d (8-F), both quantities were equal in size. Thermodynamic integration (TI) and one-step perturbation (OSP) were used to calculate the relative binding affinity of the modulators. The OSP calculations had a higher predictive power than those from TI, and combined with the shorter total simulation time, we found the OSP method to be more effective for this setup. Furthermore, from the molecular dynamics simulations, we extracted the enthalpies and entropies, and along with the ITC data, this suggested that the differences in binding free energies are largely explained by the direct ligand-surrounding enthalpies. Furthermore, we used the OSP setup to predict binding affinities for a series of polysubstituted fluorine compounds and monosubstituted methyl compounds and used these predictions to characterize the modulator binding pocket for this scaffold of positive allosteric modulators.
PMID: 25420075
DOI: 10.1021/ci500559b -
Synthesis, Pharmacological and Structural Characterization, and Thermodynamic Aspects of GluA2-Positive Allosteric Modulators with a 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide Scaffold
J. Med. Chem., 2013, 56 (21), pp 8736–8745
Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer’s disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most…
Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer’s disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a Kd of 0.35 μM (ΔH = −7.5 kcal/mol and −TΔS = −1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the cyclopropyl group of 3 and the backbone of Phe495 and Met496.
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The intracellular distal tail of the Na+/H+ exchanger NHE1 is intrinsically disordered: implications for NHE1 trafficking
Biochemistry. 2011 May 3;50(17):3469-80. Epub 2011 Apr 8.
Intrinsic disorder is important for protein regulation, yet its role in regulation of ion transport proteins is essentially uninvestigated. The ubiquitous plasma membrane carrier protein Na(+)/H(+) Exchanger isoform 1 (NHE1) plays pivotal roles in cellular pH and volume homeostasis, and its dysfunction is implicated in several clinically important diseases. This study shows, for the first time for any carrier protein, that the distal part of the C-terminal intracellular tail (the cdt, residues…
Intrinsic disorder is important for protein regulation, yet its role in regulation of ion transport proteins is essentially uninvestigated. The ubiquitous plasma membrane carrier protein Na(+)/H(+) Exchanger isoform 1 (NHE1) plays pivotal roles in cellular pH and volume homeostasis, and its dysfunction is implicated in several clinically important diseases. This study shows, for the first time for any carrier protein, that the distal part of the C-terminal intracellular tail (the cdt, residues V686-Q815) from human (h) NHE1 is intrinsically disordered. Further, we experimentally demonstrated the presence of a similar region of intrinsic disorder (ID) in NHE1 from the teleost fish Pleuronectes americanus (paNHE1), and bioinformatic analysis suggested ID to be conserved in the NHE1 family. The sequential variation in structure propensity as determined by NMR, but not the amplitude, was largely conserved between the h- and paNHE1cdt. This suggests that both proteins contain molecular recognition features (MoRFs), i.e., local, transiently formed structures within an ID region. The functional relevance of the most conserved MoRF was investigated by introducing a point mutation that significantly disrupted the putative binding feature. When this mutant NHE1 was expressed in full length NHE1 in AP1 cells, it exhibited impaired trafficking to the plasma membrane. This study demonstrated that the distal regulatory domain of NHE1 is intrinsically disordered yet contains conserved regions of transient structure. We suggest that normal NHE1 function depends on a protein recognition element within the ID region that may be linked to NHE1 trafficking via an acidic ER export motif.
Andre forfattereSe udgivelse -
Temperature-dependent structural changes in intrinsically disordered proteins: formation of alpha-helices or loss of polyproline II?
Protein Sci. 2010 Aug;19(8):1555-64.
Structural characterization of intrinsically disordered proteins (IDPs) is mandatory for deciphering their potential unique physical and biological properties. A large number of circular dichroism (CD) studies have demonstrated that a structural change takes place in IDPs with increasing temperature, which most likely reflects formation of transient alpha-helices or loss of polyproline II (PPII) content. Using three IDPs, ACTR, NHE1, and Spd1, we show that the temperature-induced structural…
Structural characterization of intrinsically disordered proteins (IDPs) is mandatory for deciphering their potential unique physical and biological properties. A large number of circular dichroism (CD) studies have demonstrated that a structural change takes place in IDPs with increasing temperature, which most likely reflects formation of transient alpha-helices or loss of polyproline II (PPII) content. Using three IDPs, ACTR, NHE1, and Spd1, we show that the temperature-induced structural change is common among IDPs and is accompanied by a contraction of the conformational ensemble. This phenomenon was explored at residue resolution by multidimensional NMR spectroscopy. Intrinsic chemical shift referencing allowed us to identify regions of transiently formed helices and their temperature-dependent changes in helicity. All helical regions were found to lose rather than gain helical structures with increasing temperature, and accordingly these were not responsible for the change in the CD spectra. In contrast, the nonhelical regions exhibited a general temperature-dependent structural change that was independent of long-range interactions. The temperature-dependent CD spectroscopic signature of IDPs that has been amply documented can be rationalized to represent redistribution of the statistical coil involving a general loss of PPII conformations.
Andre forfattereSe udgivelse -
Positive Allosteric Modulators of AMPA Receptors Belonging to 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-substituted 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides
J. Med. Chem. 2014, 57: 9539-53
PMID: 25375781
Fag/kurser
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Basic Patent Course, Novo Nordisk A/S
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Managing the Project, level 2, Novo Nordisk A/S
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Operate the CMC Project (Coordinator course), Novo Nordisk A/S
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Outsourcing: Communication, Mannaz
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Outsourcing: Cultural Awareness, Aperian Global
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PRINCE2 AGILE Practitioner, Metier
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PRINCE2 Foundation, Metier
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PRINCE2 Practitioner, Metier
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Project Management for Ph.D Students in Pharmaceutical Sciences
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Setting Direction for the CMC Project, Novo Nordisk A/S
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cLEAN 1 star (Project Management), Novo Nordisk A/S
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Udmærkelser og priser
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Novo Scholarship Programme 2008
Novo Nordisk A/S
Received a full 12 month scholarship (DKK 72,000).
Sprog
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Danish
Modersmåls- eller tosprogsfærdighed
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English
Komplet professionel færdighed
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French
Begrænset praktisk færdighed
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Latin
Elementær færdighed
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German
Elementær færdighed
Flere aktiviteter af Ann-Beth
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I am honored to receive the award as “CEO of the year” last night at the annual Danish Biotech Spring Gala. This award also reflects the high…
I am honored to receive the award as “CEO of the year” last night at the annual Danish Biotech Spring Gala. This award also reflects the high…
Ann-Beth Nørholm synes godt om dette
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Looking forward to speak tomorrow at the #ESOF2024 #EUTalentFair2024 about our board game on Grant Writing. Thank you #ESOF for the opportunity.
Looking forward to speak tomorrow at the #ESOF2024 #EUTalentFair2024 about our board game on Grant Writing. Thank you #ESOF for the opportunity.
Ann-Beth Nørholm synes godt om dette
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Come join our fantastic team! We are looking for a QA Manager GMP to our office in Hørsholm, Denmark. Read more about the position and apply…
Come join our fantastic team! We are looking for a QA Manager GMP to our office in Hørsholm, Denmark. Read more about the position and apply…
Ann-Beth Nørholm synes godt om dette
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Carl Borrebaeck, Jens Lindberg and Hans Jeppsson, Ph.D. dicuss dealmaking and strategic partnerships🤝 The panel emphazises the importance of ”meet…
Carl Borrebaeck, Jens Lindberg and Hans Jeppsson, Ph.D. dicuss dealmaking and strategic partnerships🤝 The panel emphazises the importance of ”meet…
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Just returned from the 10th RWE, Market Access, Pricing & Reimbursement Global Congress 2024 in London, where I had the opportunity to speak about…
Just returned from the 10th RWE, Market Access, Pricing & Reimbursement Global Congress 2024 in London, where I had the opportunity to speak about…
Ann-Beth Nørholm synes godt om dette
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I am thrilled to share that I will be leading the Biopolymers and Redox Enzymes group at the Department of Geosciences and Natural Resource…
I am thrilled to share that I will be leading the Biopolymers and Redox Enzymes group at the Department of Geosciences and Natural Resource…
Ann-Beth Nørholm synes godt om dette
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This morning MC2 Therapeutics announced positive feedback from our pre-IND meeting with the FDA concerning our phase 2 stage first-in-class oral drug…
This morning MC2 Therapeutics announced positive feedback from our pre-IND meeting with the FDA concerning our phase 2 stage first-in-class oral drug…
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There is a first time for everything when you are building a company. This time it is a interview with our local business support agency -…
There is a first time for everything when you are building a company. This time it is a interview with our local business support agency -…
Ann-Beth Nørholm synes godt om dette
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Today marks Svitzer’s first day of trading and official listing on Nasdaq Copenhagen A/S (Nasdaq: SVITZR) following completion of A.P. Moller -…
Today marks Svitzer’s first day of trading and official listing on Nasdaq Copenhagen A/S (Nasdaq: SVITZR) following completion of A.P. Moller -…
Ann-Beth Nørholm synes godt om dette
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A complete honour! The Vicore Pharma AB team was awarded the European Pulmonary Fibrosis Federation (EU-PFF) ‘best poster’ certificate for our…
A complete honour! The Vicore Pharma AB team was awarded the European Pulmonary Fibrosis Federation (EU-PFF) ‘best poster’ certificate for our…
Ann-Beth Nørholm synes godt om dette