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Article ; Online: Identification of ß-Glucocerebrosidase Activators for Glucosylceramide hydrolysis.

Schulze, Monika-Sarah E D / Scholz, Diana / Jnoff, Eric / Hall, Adrian / Melin, Jonathan / Sands, Zara A / Rodriguez, Elizabeth / Andre, Veronique M

ChemMedChem

2024 Volume 19, Issue 7, Page(s) e202300548

Abstract: Several novel chemical series were identified that modulate glucocerebrosidase (GCase). Compounds from these series are active on glucosylceramide, unlike other known GCase modulators. We obtained GCase crystal structures with two compounds that have ... ...

Abstract	Several novel chemical series were identified that modulate glucocerebrosidase (GCase). Compounds from these series are active on glucosylceramide, unlike other known GCase modulators. We obtained GCase crystal structures with two compounds that have distinct chemotypes. Positive allosteric modulators bind to a site on GCase and induce conformational changes, but also induce an equilibrium state between monomer and dimer.
MeSH term(s)	Humans ; Glucosylceramidase/chemistry ; Glucosylceramidase/metabolism ; Glucosylceramides ; Hydrolysis ; Gaucher Disease/drug therapy
Chemical Substances	Glucosylceramidase (EC 3.2.1.45) ; Glucosylceramides
Language	English
Publishing date	2024-02-21
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2218496-X
ISSN	1860-7187 ; 1860-7179
ISSN (online)	1860-7187
ISSN	1860-7179
DOI	10.1002/cmdc.202300548
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Zs.A 6280: Show issues

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Article ; Online: PlayMolecule CrypticScout: Predicting Protein Cryptic Sites Using Mixed-Solvent Molecular Simulations.

Martinez-Rosell, Gerard / Lovera, Silvia / Sands, Zara A / De Fabritiis, Gianni

Journal of chemical information and modeling

2020 Volume 60, Issue 4, Page(s) 2314–2324

Abstract: Cryptic pockets are protein cavities that remain hidden in resolved apo structures and generally require the presence of a co-crystallized ligand to become visible. Finding new cryptic pockets is crucial for structure-based drug discovery to identify new ...

Abstract	Cryptic pockets are protein cavities that remain hidden in resolved apo structures and generally require the presence of a co-crystallized ligand to become visible. Finding new cryptic pockets is crucial for structure-based drug discovery to identify new ways of modulating protein activity and thus expand the druggable space. We present here a new method and associated web application leveraging mixed-solvent molecular dynamics (MD) simulations using benzene as a hydrophobic probe to detect cryptic pockets. Our all-atom MD-based workflow was systematically tested on 18 different systems and 5 additional kinases and represents the largest validation study of this kind. CrypticScout identifies benzene probe binding hotspots on a protein surface by mapping probe occupancy, residence time, and the benzene occupancy reweighed by the residence time. The method is presented to the scientific community in a web application available via www.playmolecule.org using a distributed computing infrastructure to perform the simulations.
MeSH term(s)	Binding Sites ; Hydrophobic and Hydrophilic Interactions ; Ligands ; Molecular Dynamics Simulation ; Solvents
Chemical Substances	Ligands ; Solvents
Language	English
Publishing date	2020-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.9b01209
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Zs.A 1230: Show issues

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Article ; Online: Further evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein.

Wood, Martyn D / Sands, Zara A / Vandenplas, Catherine / Gillard, Michel

Epilepsia

2018 Volume 59, Issue 9, Page(s) e147–e151

Abstract: Brivaracetam (BRV) and levetiracetam (LEV) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A (SV2A) protein. BRV differs from LEV in preclinical studies in that it exhibits a more potent and complete seizure protection ... ...

Abstract	Brivaracetam (BRV) and levetiracetam (LEV) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A (SV2A) protein. BRV differs from LEV in preclinical studies in that it exhibits a more potent and complete seizure protection across animal models. We reported previously that an allosteric modulator of the SV2A protein had differential effects on BRV compared with LEV, suggesting that they act at different sites or with different conformations of the SV2A protein. If this is the case, then we hypothesized that mutations of specific amino acids in the SV2A protein may have differential effects on BRV and LEV binding by the modulator. Mutation of some amino acids identified previously in the binding site of racetams to the SV2A protein had marked effects on binding of both [
MeSH term(s)	Anilides/pharmacology ; Anticonvulsants/pharmacology ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Levetiracetam/pharmacology ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; Mutation/genetics ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Protein Binding/drug effects ; Protein Binding/genetics ; Pyrrolidinones/pharmacology ; Radioligand Assay ; Transfection ; Tritium/pharmacokinetics
Chemical Substances	4-(3,5-dimethylphenyl)-N-(2-methoxyphenyl)-3-methylbutanamide ; Anilides ; Anticonvulsants ; Membrane Glycoproteins ; Nerve Tissue Proteins ; Pyrrolidinones ; Tritium (10028-17-8) ; SV2A protein, human (148845-93-6) ; Levetiracetam (44YRR34555) ; brivaracetam (U863JGG2IA)
Language	English
Publishing date	2018-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	216382-2
ISSN	1528-1167 ; 0013-9580
ISSN (online)	1528-1167
ISSN	0013-9580
DOI	10.1111/epi.14532
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Zs.A 517: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 475: Show issues

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Article: A Numbering System for MFS Transporter Proteins.

Lee, Joanna / Sands, Zara A / Biggin, Philip C

Frontiers in molecular biosciences

2016 Volume 3, Page(s) 21

Abstract: The Major Facilitator Superfamily (MFS) is one of the largest classes of secondary active transporters and is widely expressed in many domains of life. It is characterized by a common 12-transmembrane helix motif that allows the selective transport of a ... ...

Abstract	The Major Facilitator Superfamily (MFS) is one of the largest classes of secondary active transporters and is widely expressed in many domains of life. It is characterized by a common 12-transmembrane helix motif that allows the selective transport of a vast range of diverse substrates across the membrane. MFS transporters play a central role in many physiological processes and are increasingly recognized as potential drug targets. Despite intensive efforts, there are still only a handful of crystal structures and therefore homology modeling is likely to be a necessary process for providing models to interpret experiments for many years to come. However, the diversity of sequences and the multiple conformational states these proteins can exist in makes the process significantly more complicated, especially for sequences for which there is very little sequence identity to known templates. Inspired by the approach adopted many years ago for GPCRs, we have analyzed the large number of MFS sequences now available alongside the current structural information to propose a series of conserved contact points that can provide additional guidance for the homology modeling process. To enable cross-comparison across MFS models we also present a numbering scheme that can be used to provide a point of reference within each of the 12 transmembrane regions.
Language	English
Publishing date	2016-06-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2016.00021
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Article ; Online: Reconstruction of apo A2A receptor activation pathways reveal ligand-competent intermediates and state-dependent cholesterol hotspots.

Lovera, Silvia / Cuzzolin, Alberto / Kelm, Sebastian / De Fabritiis, Gianni / Sands, Zara A

Scientific reports

2019 Volume 9, Issue 1, Page(s) 14199

Abstract: G-protein coupled receptors (GPCRs) play a pivotal role in transmitting signals at the cellular level. Structural insights can be exploited to support GPCR structure-based drug discovery endeavours. Despite advances in GPCR crystallography, active state ... ...

Abstract	G-protein coupled receptors (GPCRs) play a pivotal role in transmitting signals at the cellular level. Structural insights can be exploited to support GPCR structure-based drug discovery endeavours. Despite advances in GPCR crystallography, active state structures are scarce. Molecular dynamics (MD) simulations have been used to explore the conformational landscape of GPCRs. Efforts have been made to retrieve active state conformations starting from inactive structures, however to date this has not been possible without using an energy bias. Here, we reconstruct the activation pathways of the apo adenosine receptor (A2A), starting from an inactive conformation, by applying adaptive sampling MD combined with a goal-oriented scoring function. The reconstructed pathways reconcile well with experiments and help deepen our understanding of A2A regulatory mechanisms. Exploration of the apo conformational landscape of A2A reveals the existence of ligand-competent states, active intermediates and state-dependent cholesterol hotspots of relevance for drug discovery. To the best of our knowledge this is the first time an activation process has been elucidated for a GPCR starting from an inactive structure only, using a non-biased MD approach, opening avenues for the study of ligand binding to elusive yet pharmacologically relevant GPCR states.
MeSH term(s)	Adenosine A2 Receptor Agonists/chemistry ; Cholesterol/chemistry ; Cholesterol/genetics ; Drug Discovery ; Humans ; Ligands ; Molecular Dynamics Simulation ; Protein Conformation ; Receptor, Adenosine A2A/chemistry ; Receptor, Adenosine A2A/genetics ; Receptor, Adenosine A2A/ultrastructure ; Receptors, G-Protein-Coupled/agonists ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/genetics
Chemical Substances	Adenosine A2 Receptor Agonists ; Ligands ; Receptor, Adenosine A2A ; Receptors, G-Protein-Coupled ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2019-10-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-50752-6
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Article: Accelerating GPCR Drug Discovery With Conformation-Stabilizing VHHs.

Laeremans, Toon / Sands, Zara A / Claes, Pieter / De Blieck, Ann / De Cesco, Stephane / Triest, Sarah / Busch, Andreas / Felix, David / Kumar, Abhinav / Jaakola, Veli-Pekka / Menet, Christel

Frontiers in molecular biosciences

2022 Volume 9, Page(s) 863099

Abstract: The human genome encodes 850 G protein-coupled receptors (GPCRs), half of which are considered potential drug targets. GPCRs transduce extracellular stimuli into a plethora of vital physiological processes. Consequently, GPCRs are an attractive drug ... ...

Abstract	The human genome encodes 850 G protein-coupled receptors (GPCRs), half of which are considered potential drug targets. GPCRs transduce extracellular stimuli into a plethora of vital physiological processes. Consequently, GPCRs are an attractive drug target class. This is underlined by the fact that approximately 40% of marketed drugs modulate GPCRs. Intriguingly 60% of non-olfactory GPCRs have no drugs or candidates in clinical development, highlighting the continued potential of GPCRs as drug targets. The discovery of small molecules targeting these GPCRs by conventional high throughput screening (HTS) campaigns is challenging. Although the definition of success varies per company, the success rate of HTS for GPCRs is low compared to other target families (Fujioka and Omori, 2012; Dragovich et al., 2022). Beyond this, GPCR structure determination can be difficult, which often precludes the application of structure-based drug design approaches to arising HTS hits. GPCR structural studies entail the resource-demanding purification of native receptors, which can be challenging as they are inherently unstable when extracted from the lipid matrix. Moreover, GPCRs are flexible molecules that adopt distinct conformations, some of which need to be stabilized if they are to be structurally resolved. The complexity of targeting distinct therapeutically relevant GPCR conformations during the early discovery stages contributes to the high attrition rates for GPCR drug discovery programs. Multiple strategies have been explored in an attempt to stabilize GPCRs in distinct conformations to better understand their pharmacology. This review will focus on the use of camelid-derived immunoglobulin single variable domains (VHHs) that stabilize disease-relevant pharmacological states (termed ConfoBodies by the authors) of GPCRs, as well as GPCR:signal transducer complexes, to accelerate drug discovery. These VHHs are powerful tools for supporting in vitro screening, deconvolution of complex GPCR pharmacology, and structural biology purposes. In order to demonstrate the potential impact of ConfoBodies on translational research, examples are presented of their role in active state screening campaigns and structure-informed rational design to identify
Language	English
Publishing date	2022-05-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2022.863099
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Article ; Online: Reconstruction of apo A2A receptor activation pathways reveal ligand-competent intermediates and state-dependent cholesterol hotspots

Silvia Lovera / Alberto Cuzzolin / Sebastian Kelm / Gianni De Fabritiis / Zara A. Sands

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 10

Abstract: Abstract G-protein coupled receptors (GPCRs) play a pivotal role in transmitting signals at the cellular level. Structural insights can be exploited to support GPCR structure-based drug discovery endeavours. Despite advances in GPCR crystallography, ... ...

Abstract	Abstract G-protein coupled receptors (GPCRs) play a pivotal role in transmitting signals at the cellular level. Structural insights can be exploited to support GPCR structure-based drug discovery endeavours. Despite advances in GPCR crystallography, active state structures are scarce. Molecular dynamics (MD) simulations have been used to explore the conformational landscape of GPCRs. Efforts have been made to retrieve active state conformations starting from inactive structures, however to date this has not been possible without using an energy bias. Here, we reconstruct the activation pathways of the apo adenosine receptor (A2A), starting from an inactive conformation, by applying adaptive sampling MD combined with a goal-oriented scoring function. The reconstructed pathways reconcile well with experiments and help deepen our understanding of A2A regulatory mechanisms. Exploration of the apo conformational landscape of A2A reveals the existence of ligand-competent states, active intermediates and state-dependent cholesterol hotspots of relevance for drug discovery. To the best of our knowledge this is the first time an activation process has been elucidated for a GPCR starting from an inactive structure only, using a non-biased MD approach, opening avenues for the study of ligand binding to elusive yet pharmacologically relevant GPCR states.
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publishing date	2019-10-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Accelerating GPCR Drug Discovery With Conformation-Stabilizing VHHs

Toon Laeremans / Zara A. Sands / Pieter Claes / Ann De Blieck / Stephane De Cesco / Sarah Triest / Andreas Busch / David Felix / Abhinav Kumar / Veli-Pekka Jaakola / Christel Menet

Frontiers in Molecular Biosciences, Vol

2022 Volume 9

Abstract	The human genome encodes 850 G protein-coupled receptors (GPCRs), half of which are considered potential drug targets. GPCRs transduce extracellular stimuli into a plethora of vital physiological processes. Consequently, GPCRs are an attractive drug target class. This is underlined by the fact that approximately 40% of marketed drugs modulate GPCRs. Intriguingly 60% of non-olfactory GPCRs have no drugs or candidates in clinical development, highlighting the continued potential of GPCRs as drug targets. The discovery of small molecules targeting these GPCRs by conventional high throughput screening (HTS) campaigns is challenging. Although the definition of success varies per company, the success rate of HTS for GPCRs is low compared to other target families (Fujioka and Omori, 2012; Dragovich et al., 2022). Beyond this, GPCR structure determination can be difficult, which often precludes the application of structure-based drug design approaches to arising HTS hits. GPCR structural studies entail the resource-demanding purification of native receptors, which can be challenging as they are inherently unstable when extracted from the lipid matrix. Moreover, GPCRs are flexible molecules that adopt distinct conformations, some of which need to be stabilized if they are to be structurally resolved. The complexity of targeting distinct therapeutically relevant GPCR conformations during the early discovery stages contributes to the high attrition rates for GPCR drug discovery programs. Multiple strategies have been explored in an attempt to stabilize GPCRs in distinct conformations to better understand their pharmacology. This review will focus on the use of camelid-derived immunoglobulin single variable domains (VHHs) that stabilize disease-relevant pharmacological states (termed ConfoBodies by the authors) of GPCRs, as well as GPCR:signal transducer complexes, to accelerate drug discovery. These VHHs are powerful tools for supporting in vitro screening, deconvolution of complex GPCR pharmacology, and structural biology ...
Keywords	active state ; biosensor ; ConfoBody ; conformation ; conformer ; GPCR ; Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Crystal structure of dopamine D1 receptor in complex with G protein and a non-catechol agonist

Bingfa Sun / Dan Feng / Matthew Ling-Hon Chu / Inbar Fish / Silvia Lovera / Zara A. Sands / Sebastian Kelm / Anne Valade / Martyn Wood / Tom Ceska / Tong Sun Kobilka / Florence Lebon / Brian K. Kobilka

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 9

Abstract: Recently, a class of non-catechol Dopamine D1 receptor (D1R) selective agonists with novel scaffold and improved pharmacological properties were reported. Here, authors report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a ... ...

Abstract	Recently, a class of non-catechol Dopamine D1 receptor (D1R) selective agonists with novel scaffold and improved pharmacological properties were reported. Here, authors report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 which explains the selectivity of this scaffold for D1R over other aminergic receptors and the mechanism of activating D1R.
Keywords	Science ; Q
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Crystal structure of dopamine D1 receptor in complex with G protein and a non-catechol agonist.

Sun, Bingfa / Feng, Dan / Chu, Matthew Ling-Hon / Fish, Inbar / Lovera, Silvia / Sands, Zara A / Kelm, Sebastian / Valade, Anne / Wood, Martyn / Ceska, Tom / Kobilka, Tong Sun / Lebon, Florence / Kobilka, Brian K

Nature communications

2021 Volume 12, Issue 1, Page(s) 3305

Abstract: Dopamine D1 receptor (D1R) is an important drug target implicated in many psychiatric and neurological disorders. Selective agonism of D1R are sought to be the therapeutic strategy for these disorders. Most selective D1R agonists share a dopamine-like ... ...

Abstract	Dopamine D1 receptor (D1R) is an important drug target implicated in many psychiatric and neurological disorders. Selective agonism of D1R are sought to be the therapeutic strategy for these disorders. Most selective D1R agonists share a dopamine-like catechol moiety in their molecular structure, and their therapeutic potential is therefore limited by poor pharmacological properties in vivo. Recently, a class of non-catechol D1R selective agonists with a distinct scaffold and pharmacological properties were reported. Here, we report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 at 3.8 Å resolution. The structure reveals the ligand bound to D1R in an extended conformation, spanning from the orthosteric site to extracellular loop 2 (ECL2). Structural analysis reveals that the unique features of D1R ligand binding pocket explains the remarkable selectivity of this scaffold for D1R over other aminergic receptors, and sheds light on the mechanism for D1R activation by the non-catechol agonist.
MeSH term(s)	Binding Sites ; Crystallography, X-Ray ; GTP-Binding Protein alpha Subunits, Gs/chemistry ; Humans ; In Vitro Techniques ; Ligands ; Models, Molecular ; Molecular Dynamics Simulation ; Protein Binding ; Protein Conformation ; Protein Engineering ; Protein Structure, Quaternary ; Receptors, Dopamine D1/agonists ; Receptors, Dopamine D1/chemistry ; Recombinant Proteins/chemistry
Chemical Substances	DRD1 protein, human ; Ligands ; Receptors, Dopamine D1 ; Recombinant Proteins ; GTP-Binding Protein alpha Subunits, Gs (EC 3.6.5.1)
Language	English
Publishing date	2021-06-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-23519-9
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