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Article ; Online: PROTAC targeted protein degraders: the past is prologue.

Békés, Miklós / Langley, David R / Crews, Craig M

2022 Volume 21, Issue 3, Page(s) 181–200

Abstract: Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. In the 20 years since the concept of ... ...

Abstract	Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. In the 20 years since the concept of a proteolysis-targeting chimera (PROTAC) molecule harnessing the ubiquitin-proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development. With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered 'undruggable'. In this Review, we summarize the first two decades of PROTAC discovery and assess the current landscape, with a focus on industry activity. We then discuss key areas for the future of TPD, including establishing the target classes for which TPD is most suitable, expanding the use of ubiquitin ligases to enable precision medicine and extending the modality beyond oncology.
MeSH term(s)	Humans ; Proteasome Endopeptidase Complex/metabolism ; Proteins/metabolism ; Proteolysis
Chemical Substances	Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Proteins
Language	English
Publishing date	2022-01-18
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2062954-0
ISSN	1474-1784 ; 1474-1776
ISSN (online)	1474-1784
ISSN	1474-1776
DOI	10.1038/s41573-021-00371-6
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Zs.A 5564: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Mutagenic Activation of Glutathione Peroxidase-4: Approaches toward Rational Design of Allosteric Drugs.

Ma, Chunyue / Chung, Daniel J / Abramson, Dylan / Langley, David R / Thayer, Kelly M

ACS omega

2022 Volume 7, Issue 34, Page(s) 29587–29597

Abstract: Glutathione peroxidase 4 (GPX4) reduces lipid hydroperoxides in lipid membranes, effectively inhibiting iron-dependent cell death or ferroptosis. The upregulation of the enzyme by the mutations at residues D21 and D23 has been suggested to be associated ... ...

Abstract	Glutathione peroxidase 4 (GPX4) reduces lipid hydroperoxides in lipid membranes, effectively inhibiting iron-dependent cell death or ferroptosis. The upregulation of the enzyme by the mutations at residues D21 and D23 has been suggested to be associated with higher protein activity, which confers more protection against neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Therefore, it has become an attractive target for treating and preventing neurodegenerative diseases. However, identifying means of mimicking the beneficial effects of these mutations distant from the active site constitutes a formidable challenge in moving toward therapeutics. In this study, we explore using molecular dynamics simulations to computationally map the conformational and energetic landscape of the wild-type GPX4 protein and three mutant variants to identify the allosteric networks of the enzyme. We present the conformational dynamic profile providing the desired signature behavior of the enzyme. We also discuss the implications of these findings for drug design efforts.
Language	English
Publishing date	2022-08-16
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.2c01289
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Article ; Online: Co-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules.

Hickey, Christopher M / Digianantonio, Katherine M / Zimmermann, Kurt / Harbin, Alicia / Quinn, Connor / Patel, Avani / Gareiss, Peter / Chapman, Amanda / Tiberi, Bernadette / Dobrodziej, Jennifer / Corradi, John / Cacace, Angela M / Langley, David R / Békés, Miklós

Nature structural & molecular biology

2024 Volume 31, Issue 2, Page(s) 311–322

Abstract: Targeted protein degradation (TPD) by PROTAC (proteolysis-targeting chimera) and molecular glue small molecules is an emerging therapeutic strategy. To expand the roster of E3 ligases that can be utilized for TPD, we describe the discovery and ... ...

Abstract	Targeted protein degradation (TPD) by PROTAC (proteolysis-targeting chimera) and molecular glue small molecules is an emerging therapeutic strategy. To expand the roster of E3 ligases that can be utilized for TPD, we describe the discovery and biochemical characterization of small-molecule ligands targeting the E3 ligase KLHDC2. Furthermore, we functionalize these KLHDC2-targeting ligands into KLHDC2-based BET-family and AR PROTAC degraders and demonstrate KLHDC2-dependent target-protein degradation. Additionally, we offer insight into the assembly of the KLHDC2 E3 ligase complex. Using biochemical binding studies, X-ray crystallography and cryo-EM, we show that the KLHDC2 E3 ligase assembles into a dynamic tetramer held together via its own C terminus, and that this assembly can be modulated by substrate and ligand engagement.
MeSH term(s)	Proteolysis ; Ubiquitin-Protein Ligases/metabolism ; Ligands
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Ligands
Language	English
Publishing date	2024-01-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/s41594-023-01146-w
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Zs.A 4101: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 56: Show issues

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Article ; Online: MORPH: a new tool for ligand design.

Beno, Brett R / Langley, David R

Journal of chemical information and modeling

2010 Volume 50, Issue 6, Page(s) 1159–1164

Abstract: A frequently employed strategy in drug discovery efforts is to replace aromatic rings in known active compounds with alternative aromatic moieties to create novel compounds with improved potency and/or adsorption, distribution, metabolism, excretion, and ...

Abstract	A frequently employed strategy in drug discovery efforts is to replace aromatic rings in known active compounds with alternative aromatic moieties to create novel compounds with improved potency and/or adsorption, distribution, metabolism, excretion, and toxicity properties. Here we introduce MORPH, which is a simple software tool for systematically modifying aromatic rings in three-dimensional models of molecules without altering the coordinates of the nonhydrogen atoms in the rings. MORPH works on individual rings as well as fused ring systems and additionally provides the ability to filter out modified compounds which do not contain hydrogen-bond donors or acceptors at specific positions on the rings or contain more or less than the desired number of heteroatoms. The MORPH program and its application to two ligands extracted from cocrystal structures with cyclin-dependent kinase 2 (CDK2)/cyclin A and CDK2 are discussed below.
MeSH term(s)	Algorithms ; Cyclin A/metabolism ; Cyclin-Dependent Kinase 2/antagonists & inhibitors ; Cyclin-Dependent Kinase 2/chemistry ; Cyclin-Dependent Kinase 2/metabolism ; Drug Design ; Ligands ; Models, Molecular ; Protein Conformation ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/metabolism ; Protein Kinase Inhibitors/pharmacology ; Pyrazoles/chemistry ; Pyrazoles/metabolism ; Pyrazoles/pharmacology ; Pyrimidines/chemistry ; Pyrimidines/metabolism ; Pyrimidines/pharmacology ; Software
Chemical Substances	3-aminopyrazole ; Cyclin A ; Ligands ; Protein Kinase Inhibitors ; Pyrazoles ; Pyrimidines ; Cyclin-Dependent Kinase 2 (EC 2.7.11.22)
Language	English
Publishing date	2010-06-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/ci9004964
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Article ; Online: Communication: Quantum polarized fluctuating charge model: a practical method to include ligand polarizability in biomolecular simulations.

Kimura, S Roy / Rajamani, Ramkumar / Langley, David R

The Journal of chemical physics

2011 Volume 135, Issue 23, Page(s) 231101

Abstract: We present a simple and practical method to include ligand electronic polarization in molecular dynamics (MD) simulation of biomolecular systems. The method involves periodically spawning quantum mechanical (QM) electrostatic potential (ESP) calculations ...

Abstract	We present a simple and practical method to include ligand electronic polarization in molecular dynamics (MD) simulation of biomolecular systems. The method involves periodically spawning quantum mechanical (QM) electrostatic potential (ESP) calculations on an extra set of computer processors using molecular coordinate snapshots from a running parallel MD simulation. The QM ESPs are evaluated for the small-molecule ligand in the presence of the electric field induced by the protein, solvent, and ion charges within the MD snapshot. Partial charges on ligand atom centers are fit through the multi-conformer restrained electrostatic potential (RESP) fit method on several successive ESPs. The RESP method was selected since it produces charges consistent with the AMBER/GAFF force-field used in the simulations. The updated charges are introduced back into the running simulation when the next snapshot is saved. The result is a simulation whose ligand partial charges continuously respond in real-time to the short-term mean electrostatic field of the evolving environment without incurring additional wall-clock time. We show that (1) by incorporating the cost of polarization back into the potential energy of the MD simulation, the algorithm conserves energy when run in the microcanonical ensemble and (2) the mean solvation free energies for 15 neutral amino acid side chains calculated with the quantum polarized fluctuating charge method and thermodynamic integration agree better with experiment relative to the Amber fixed charge force-field.
MeSH term(s)	Algorithms ; Amino Acids/chemistry ; Entropy ; Ions/chemistry ; Ligands ; Models, Chemical ; Molecular Dynamics Simulation ; Protein Binding ; Proteins/chemistry ; Quantum Theory ; Solvents/chemistry ; Static Electricity
Chemical Substances	Amino Acids ; Ions ; Ligands ; Proteins ; Solvents
Language	English
Publishing date	2011-12-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	3113-6
ISSN	1089-7690 ; 0021-9606
ISSN (online)	1089-7690
ISSN	0021-9606
DOI	10.1063/1.3671638
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Article ; Online: Expanding GPCR homology model binding sites via a balloon potential: A molecular dynamics refinement approach.

Kimura, S Roy / Tebben, Andrew J / Langley, David R

Proteins

2008 Volume 71, Issue 4, Page(s) 1919–1929

Abstract: Homology modeling of G protein-coupled receptors is becoming a widely used tool in drug discovery. However, unrefined models built using the bovine rhodopsin crystal structure as the template, often have binding sites that are too small to accommodate ... ...

Abstract	Homology modeling of G protein-coupled receptors is becoming a widely used tool in drug discovery. However, unrefined models built using the bovine rhodopsin crystal structure as the template, often have binding sites that are too small to accommodate known ligands. Here, we present a novel systematic method to refine model active sites based on a pressure-guided molecular dynamics simulation. A distinct advantage of this approach is the ability to introduce systematic perturbations in model backbone atoms in addition to side chain adjustments. The method is validated on two test cases: (1) docking of retinal into an MD-relaxed structure of opsin and (2) docking of known ligands into a homology model of the CCR2 receptor. In both cases, we show that the MD expansion algorithm makes it possible to dock the ligands in poses that agree with the crystal structure or mutagenesis data.
MeSH term(s)	Algorithms ; Animals ; Apoproteins/chemistry ; Apoproteins/metabolism ; Binding Sites ; Cattle ; Computer Simulation ; Cross-Linking Reagents/metabolism ; Hot Temperature ; Hydrogen Bonding ; Ligands ; Models, Biological ; Models, Chemical ; Models, Molecular ; Mutation ; Pressure ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, CCR2/antagonists & inhibitors ; Receptors, CCR2/chemistry ; Receptors, CCR2/metabolism ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Reproducibility of Results ; Retinaldehyde/chemistry ; Rhodopsin/chemistry ; Rhodopsin/metabolism ; Rod Opsins/chemistry ; Structure-Activity Relationship ; Time Factors
Chemical Substances	Apoproteins ; Cross-Linking Reagents ; Ligands ; Receptors, CCR2 ; Receptors, G-Protein-Coupled ; Rod Opsins ; Rhodopsin (9009-81-8) ; Retinaldehyde (RR725D715M)
Language	English
Publishing date	2008-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	806683-8
ISSN	1097-0134 ; 0887-3585
ISSN (online)	1097-0134
ISSN	0887-3585
DOI	10.1002/prot.21906
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Zs.A 2291: Show issues

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Article ; Online: Mechanistic characterization and molecular modeling of hepatitis B virus polymerase resistance to entecavir.

Walsh, Ann W / Langley, David R / Colonno, Richard J / Tenney, Daniel J

PloS one

2010 Volume 5, Issue 2, Page(s) e9195

Abstract: Background: Entecavir (ETV) is a deoxyguanosine analog competitive inhibitor of hepatitis B virus (HBV) polymerase that exhibits delayed chain termination of HBV DNA. A high barrier to entecavir-resistance (ETVr) is observed clinically, likely due to ... ...

Abstract	Background: Entecavir (ETV) is a deoxyguanosine analog competitive inhibitor of hepatitis B virus (HBV) polymerase that exhibits delayed chain termination of HBV DNA. A high barrier to entecavir-resistance (ETVr) is observed clinically, likely due to its potency and a requirement for multiple resistance changes to overcome suppression. Changes in the HBV polymerase reverse-transcriptase (RT) domain involve lamivudine-resistance (LVDr) substitutions in the conserved YMDD motif (M204V/I +/- L180M), plus an additional ETV-specific change at residues T184, S202 or M250. These substitutions surround the putative dNTP binding site or primer grip regions of the HBV RT. Methods/principal findings: To determine the mechanistic basis for ETVr, wildtype, lamivudine-resistant (M204V, L180M) and ETVr HBVs were studied using in vitro RT enzyme and cell culture assays, as well as molecular modeling. Resistance substitutions significantly reduced ETV incorporation and chain termination in HBV DNA and increased the ETV-TP inhibition constant (K(i)) for HBV RT. Resistant HBVs exhibited impaired replication in culture and reduced enzyme activity (k(cat)) in vitro. Molecular modeling of the HBV RT suggested that ETVr residue T184 was adjacent to and stabilized S202 within the LVDr YMDD loop. ETVr arose through steric changes at T184 or S202 or by disruption of hydrogen-bonding between the two, both of which repositioned the loop and reduced the ETV-triphosphate (ETV-TP) binding pocket. In contrast to T184 and S202 changes, ETVr at primer grip residue M250 was observed during RNA-directed DNA synthesis only. Experimentally, M250 changes also impacted the dNTP-binding site. Modeling suggested a novel mechanism for M250 resistance, whereby repositioning of the primer-template component of the dNTP-binding site shifted the ETV-TP binding pocket. No structural data are available to confirm the HBV RT modeling, however, results were consistent with phenotypic analysis of comprehensive substitutions of each ETVr position. Conclusions: Altogether, ETVr occurred through exclusion of ETV-TP from the dNTP-binding site, through different, novel mechanisms that involved lamivudine-resistance, ETV-specific substitutions, and the primer-template.
MeSH term(s)	Amino Acid Sequence ; Amino Acid Substitution ; Antiviral Agents/pharmacology ; Binding Sites/genetics ; Drug Resistance, Viral/genetics ; Guanine/analogs & derivatives ; Guanine/pharmacology ; Guanosine Triphosphate/chemistry ; Guanosine Triphosphate/metabolism ; Hep G2 Cells ; Hepatitis B virus/enzymology ; Hepatitis B virus/genetics ; Humans ; Hydrogen Bonding ; Kinetics ; Lamivudine/pharmacology ; Models, Molecular ; Protein Binding ; Protein Structure, Tertiary ; RNA-Directed DNA Polymerase/chemistry ; RNA-Directed DNA Polymerase/genetics ; RNA-Directed DNA Polymerase/metabolism ; Substrate Specificity ; Viral Proteins/chemistry ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Virus Replication/drug effects ; Virus Replication/genetics
Chemical Substances	Antiviral Agents ; Viral Proteins ; Lamivudine (2T8Q726O95) ; entecavir (5968Y6H45M) ; Guanine (5Z93L87A1R) ; Guanosine Triphosphate (86-01-1) ; RNA-Directed DNA Polymerase (EC 2.7.7.49)
Language	English
Publishing date	2010-02-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0009195
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Article ; Online: Uncialamycin as a novel payload for antibody drug conjugate (ADC) based targeted cancer therapy.

Chowdari, Naidu S / Pan, Chin / Rao, Chetana / Langley, David R / Sivaprakasam, Prasanna / Sufi, Bilal / Derwin, Daniel / Wang, Yichong / Kwok, Eilene / Passmore, David / Rangan, Vangipuram S / Deshpande, Shrikant / Cardarelli, Pina / Vite, Gregory / Gangwar, Sanjeev

Bioorganic & medicinal chemistry letters

2018 Volume 29, Issue 3, Page(s) 466–470

Abstract: Uncialamycin analogs were evaluated as potential cytotoxic agents in an antibody-drug conjugate (ADC) approach to treating human cancer. These analogs were synthesized using Hauser annulations of substituted phthalides as a key step. A highly potent ... ...

Abstract	Uncialamycin analogs were evaluated as potential cytotoxic agents in an antibody-drug conjugate (ADC) approach to treating human cancer. These analogs were synthesized using Hauser annulations of substituted phthalides as a key step. A highly potent uncialamycin analog 3c with a valine-citrulline dipeptide linker was conjugated to an anti-mesothelin monoclonal antibody (mAb) through lysines to generate a meso-13 conjugate. This conjugate demonstrated subnanomolar potency (IC50 = 0.88 nM, H226 cell line) in in vitro cytotoxicity experiments with good immunological specificity to mesothelin-positive lung cancer cell lines. The potency and mechanism of action of this uncialamycin class of enediyne antitumor antibiotics make them attractive payloads in ADC-based cancer therapy.
MeSH term(s)	Anthraquinones/chemistry ; Anthraquinones/pharmacology ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; Immunoconjugates/chemistry ; Immunoconjugates/pharmacology ; Lung Neoplasms/drug therapy ; Lung Neoplasms/pathology ; Models, Molecular ; Molecular Structure ; Structure-Activity Relationship
Chemical Substances	Anthraquinones ; Antibodies, Monoclonal ; Antineoplastic Agents ; Immunoconjugates ; uncialamycin
Language	English
Publishing date	2018-12-11
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2018.12.021
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Article ; Online: Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors.

Peese, Kevin M / Naidu, B Narasimhulu / Patel, Manoj / Li, Chen / Langley, David R / Terry, Brian / Protack, Tricia / Gali, Volodymyr / Lin, Zeyu / Samanta, Himadri K / Zheng, Ming / Jenkins, Susan / Dicker, Ira B / Krystal, Mark R / Meanwell, Nicholas A / Walker, Michael A

Bioorganic & medicinal chemistry letters

2019 Volume 30, Issue 3, Page(s) 126784

Abstract: A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These ... ...

Abstract	A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety was found to be the optimal amide substitute and the observed activity was rationalized with the use of calculated properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds demonstrated moderate clearance and moderate exposure.
MeSH term(s)	Amides/chemistry ; Animals ; Binding Sites ; Catalytic Domain ; Drug Resistance, Viral/drug effects ; HIV Integrase/chemistry ; HIV Integrase/genetics ; HIV Integrase/metabolism ; HIV Integrase Inhibitors/chemistry ; HIV Integrase Inhibitors/metabolism ; HIV Integrase Inhibitors/pharmacology ; HIV-1/drug effects ; HIV-1/enzymology ; Half-Life ; Heterocyclic Compounds, 3-Ring/chemistry ; Heterocyclic Compounds, 3-Ring/metabolism ; Heterocyclic Compounds, 3-Ring/pharmacology ; Humans ; Molecular Dynamics Simulation ; Mutation ; Rats ; Structure-Activity Relationship
Chemical Substances	Amides ; HIV Integrase Inhibitors ; Heterocyclic Compounds, 3-Ring ; HIV Integrase (EC 2.7.7.-) ; p31 integrase protein, Human immunodeficiency virus 1 (YY6481J2FF)
Language	English
Publishing date	2019-11-09
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2019.126784
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Article ; Online: Structure-based amelioration of PXR transactivation in a novel series of macrocyclic allosteric inhibitors of HIV-1 integrase.

Bioorganic & medicinal chemistry letters

2020 Volume 30, Issue 22, Page(s) 127531

Abstract: Previous studies have identified a series of imidazo[1,2-a]pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of ... ...

Abstract	Previous studies have identified a series of imidazo[1,2-a]pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of the pregnane-X receptor (PXR), raising the specter of induction of CYP-mediated drug disposition pathways. In an attempt to modify PXR activity without affecting anti-HIV-1 activity, rational structure-based design and modeling approaches were used. An X-ray cocrystal structure of (S,S)-1 in the PXR ligand binding domain (LBD) allowed an examination of the potential of rational structural modifications designed to abrogate PXR. The introduction of bulky basic amines at the C-8 position provided macrocyclic IZP derivatives that displayed potent HIV-1 inhibitory activity in cell culture with no detectable PXR transactivation at the highest concentration tested.
MeSH term(s)	Allosteric Regulation/drug effects ; Anti-HIV Agents/chemical synthesis ; Anti-HIV Agents/chemistry ; Anti-HIV Agents/pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; HIV Integrase Inhibitors/chemical synthesis ; HIV Integrase Inhibitors/chemistry ; HIV Integrase Inhibitors/pharmacology ; HIV-1/drug effects ; Humans ; Macrocyclic Compounds/chemical synthesis ; Macrocyclic Compounds/chemistry ; Macrocyclic Compounds/pharmacology ; Microbial Sensitivity Tests ; Molecular Structure ; Pregnane X Receptor/antagonists & inhibitors ; Pregnane X Receptor/metabolism ; Structure-Activity Relationship ; Virus Replication/drug effects
Chemical Substances	Anti-HIV Agents ; HIV Integrase Inhibitors ; Macrocyclic Compounds ; Pregnane X Receptor
Language	English
Publishing date	2020-09-02
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2020.127531
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