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7,673 results for “inhibitor”
Diffraction images for yeast 5-aminolevulinic acid dehydratase complexed with the inhibitor 5-hydroxylevulinic acid.
<p>Diffraction images for a co-crystal of 5-aminolaevulinic acid dehydratase (ALAD) from yeast with the competitive inhibitor 5-hydroxylevulinic acid extending to a resolution of 1.9 Å. The data were collected at beamline ID29 at ESRF in Feb 2002 using an ADSC detector. </p>
X-ray diffraction images of endothiapepsin complexed with the norstatine inhibitor CP-80,794.
<p>X-ray diffraction images of endothiapepsin complexed with CP-80,794 collected at ESRF beamline ID14-2 on 28th April 2001 to 0.98 Å resolution. More details in the included notes. </p>
X-ray diffraction images of endothiapepsin complexed with the inhibitor H256.
<p>X-ray diffraction images for endothiapepsin complexed with the reduced bond inhibitor H256 collected at ESRF beamline ID14-2. </p>
Atomic resolution X-ray diffraction images for endothiapepsin complexed with a cyclic statine inhibitor.
<p>X-ray diffraction images for endothiapepsin complexed with inhibitor CP-129,541. The data were collected on 29th April 2001. </p>
X-ray diffraction images of endothiapepsin complexed with the phosphostatine inhibitor PD-130,328.
<p>X-ray diffraction images collected at the ESRF (Grenoble) beamline ID14-2 using an ADSC Quantum 4R CCD detector on 9 Apr 2000. </p>
Type-II kinase inhibitors that target Parkinson's Disease-associated LRRK2
<p>This dataset includes all of the tabular data used in the tables and figures in the article. Additionally, we provide a table with key resources for data aquisition.</p> <p>Aberrant increases in kinase activity of leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson’s disease (PD). Numerous LRRK2-selective type-I kinase inhibitors have been developed and some have entered clinical trials. In this study, we present the first LRRK2-selective type-II kinase inhibitors. Targeting the inactive conformation of LRRK2 is functionally distinct from targeting the active-like conformation using type-I inhibitors. We designed these inhibitors using a combinatorial chemistry approach fusing selective LRRK2 type-I and promiscuous type-II inhibitors by iterative cycles of synthesis supported by structural biology and activity testing. Our current lead structures are selective and potent LRRK2 inhibitors. Through cellular assays, cryo-electron microscopy structural analysis, and in vitro motility assays, we show that our inhibitors stabilize the open, inactive kinase conformation. These new conformation-specific compounds will be invaluable as tools to study LRRK2’s function and regulation, and expand the potential therapeutic options for PD.</p>
Allosteric Modulation of YAP/TAZ-TEAD Interaction by Palmitoylation and Small Molecule Inhibitors
<p>The tar file contains 3 directories, each of which contains all of the simulation input files (pdb, prmtop, inpcrd) and trajectory files (nc) for the simulations run. </p><ol><li>TEAD_Only: Simulations of the TEAD protein in the apo, inhibitor(inh)-bound, palmitate(plt)-bound, or palmitic acid(plm)-bound form </li><li>YAP-TEAD: Simulations of the YAP-TEAD heterodimer in the apo, inhibitor(inh)-bound, palmitate(plt)-bound, or palmitic acid(plm)-bound form </li><li>TAZ-TEAD: Simulations of the TAZ-TEAD heterodimer in the apo, inhibitor(inh)-bound, palmitate(plt)-bound, or palmitic acid(plm)-bound form </li></ol>
Inhibition of Parkinson's Disease-related LRRK2 by type-I and type-II kinase inhibitors: activity and structures
<p>Mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are a common cause of familial Parkinson’s Disease (PD), and a risk factor for the sporadic form. Increased kinase activity has been shown in both familial and sporadic PD patients. This has made LRRK2 kinase inhibitors a major focus of drug development efforts in PD. Although significant progress has been made in understanding the structural biology of LRRK2, there are no available structures of LRRK2 inhibitor complexes. To this end, we solved cryo-EM structures of LRRK2, wild-type and PD-linked mutants, bound to the LRRK2-specific type-I inhibitor MLi-2 and the broad-spectrum type-II inhibitor GZD-824. Our structures revealed LRRK2’s kinase in the active-like state, stabilized by type-I inhibitor interactions, and an inactive DYG-out type-II inhibitor complex. The structures also showed how inhibitor-induced conformational changes are affected by the N-terminal half of LRRK2. The structural models provide a template for the rational development of LRRK2 kinase inhibitors covering both canonical inhibitor binding modes.</p>
Tabular and image data of article "Morphing cholinesterase inhibitor amiridine into multipotent drugs for the treatment of Alzheimer's disease"
<p>The search for novel drugs to address the medical needs of Alzheimer’s disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more<br>comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N-methyl-D-aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridinebased drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy.</p> <p><strong>Table 1. </strong>hBChE inhibitory activities of 5c-d, 7c and 7 g and reference compounds (amiridine hydrochloride and THA); their cytotoxicity profile on SH-SY5Y cell line, and predictions of BBB penetration.</p> <p>T<strong>able 2</strong>. Relative inhibitions (RIs) of 5c-d and 7 m and reference compound memantine at recombinant human GluN1/GluN2B NMDA receptor expressed in HEK293 cells.</p> <p><strong>Fig_1</strong>. Chemical structures of rivastigmine, galantamine, and tacrine as representatives of cholinesterase inhibitors. Approaches to novel drugs for AD treatment on the selected candidates are displayed.</p> <p><strong>Fig_2</strong>. Examples of previously published amiridine-based derivatives and design strategy applied in the current study below, using various pharmacophores.</p> <p><strong>Fig_3</strong>. Top scored docking pose of 5b (A) and 5d (B) highlighting the key findings responsible for compound activity/inactivity. For the sake of clarity, superimposed ligands are aligned in the Fig. C with respect to key amino acid residue W82 to demonstrate the binding difference. Compounds 5b and 5d are colored in salmon and yellow, respectively. Essential amino acid residues responsible for ligand anchoring are rendered in green. Important interactions of different origin are displayed with dashed black lines. The figure was created with The PyMOL Molecular Graphics System, v. 2.5.2.</p> <p><strong>Scheme 1</strong>. Preparation of the amiridine-based compounds 5a-d. Reagents and conditions: <strong>a)</strong> 2-chloroacetyl chloride (4 eq.), CHCl3, 90 ◦C, overnight, 8, 54%, 11, 90%, 12, 52%; <strong>b)</strong> CH3CN, K2CO3, KI, reflux, 3 h, 5a, 54%, 5b, 54%; <strong>c)</strong> amiridine (1.1 eq), CH3CN, K2CO3, KI, reflux, overnight, 5c, 48%, 5d, 41%.</p> <p><strong>Scheme 2</strong>. Preparation of intermediate 13 and final compound 6. Reagents and conditions: <strong>a)</strong> potassium phthalimide, CH3CN, reflux, 3 h, then an excess of NH2NH2⋅H2O, reflux, overnight, 57%; <strong>b)</strong> DMF, TEA, BOP, room temperature, 2 days, 86%.</p> <p><strong>Scheme 3</strong>. Preparation of amiridine-benzothiazole derivatives 7a-m. Reagents and conditions: <strong>a)</strong> for 7a: 2-chlorobenzothiazole, 110 ◦C, overnight, 32%; for 7b-m: corresponding 2-chlorobenzothiazole, DIPEA, 100 ◦C, overnight, 21–77%.</p>
Fig. 1 in Protease inhibitors of fodder plants as a factor of immune response influencing the physiological state of the potato ladybird beetle Henosepilachna vigintioctomaculata (Coleoptera: Coccinellidae)
Fig. 1. Analysis of the population of the potato ladybird beetle with the species-specific PCR-markers of the gene COI mtDNA. А – species-specific marker for H. vigintioctopunctata, 400 b.p.; Б – species-specific marker for H. vigintioctomaculata, 406 b.p.; М – marker of the lengths of fragments 100 b.p. ladder; 1–3 – Primorsky krai: Chuguevsky district; 4–6 – Amurskaya oblast; 7–17 – Primorsky krai: Timiryazevsky.
Fig. 3 in Protease inhibitors of fodder plants as a factor of immune response influencing the physiological state of the potato ladybird beetle Henosepilachna vigintioctomaculata (Coleoptera: Coccinellidae)
Fig. 3. Sinergetic activity of the protainases of trypsin type (in an insect) and trypsin inhibitors (in a plant) in the course of feeding on different potato varieties.
HDAC6 screening dataset using tau-based substrate in an enzymatic assay yields selective inhibitors and activators
<p><strong>Structure and information of the data file</strong></p> <p>DATA SET; Contains the information to which data set this information belongs. There are four possibilities denoted 1 to 4. Data set1: Enzymatic assay of human HDAC6 with commercial peptide substrate. Data set2: Enzymatic assay of human HDAC6 with custom peptide substrate. Data set3: Hit confirmation of the active molecules of the enzymatic assay of human HDAC6 with custom peptide substrate. Data set4: Determination of IC50 values for inhibition of enzymatic assay of human HDAC6 with custom peptide substrate.</p> <p>INTERNAL NAME; An internal name which enables identification of the compound within data sets from Fraunhofer ITMP ScreeningPort.</p> <p>TYPE; Type of data. Either 'inhibition' for normalized inhibition values or 'IC50' for enzymatic IC50.</p> <p>RELATION; Relation between TYPE and VALUE, always '='.</p> <p>VALUE; Value of the normalized inhibition or the enzymatic IC50.</p> <p>UNITS; Unit of the value. Either '%' for the normalized inhibition or 'uM' for the enzymatic IC50.</p> <p>NAME; Trade name of the chemical compound.</p> <p>SMILES; The canonical Smile of the chemical compound.</p> <p> </p> <p><strong>A</strong><strong>bstract</strong></p> <p>Histone deacetylase 6 (HDAC6) and HDAC10 are unique among the other HDACs as they consist of two domains instead of one. Only in the case of HDAC6 both domains are active resulting in a number of unique deacetylase reactions. Interestingly, HDAC6 can regulate the microtubule network and plays a role in the degradation of misfolded and aggregated proteins. We therefore developed a substrate (Boc-Ile-Asp-(Dimethyl)Lys-(Ac)Lys-aminoluciferin) based on a critical acetylation site of misfolded human Tau, a hallmark of Alzheimer’s Disease. This substrate was used to screen a 5632 compound encompassing repurposing library at 10 µM in a coupled, luminescence based assay. The assay was miniaturised to 10 µL per enzymatic reaction. For comparison, a generic HDAC substrate (BOC-Gly-(Ac)Lys-aminoluciferin) was also used to screen the same library. Both substrates rely on a cascade of enzymatic reactions. First, HDAC6 deacetylates the substrate followed by cleavage of aminluciferin from the peptide by porcine Trypsin and conversion of the aminoluciferin using firefly Luciferase. Compounds with an activity of at least 75% inhibition against the custom human Tau based substrate were confirmed in triplicates at the screening concentration of 10 µM. Confirmed hits, activity of at least 75%, where analysed in 8 point or 15 point dose response curves, depending on their activity. The data presented here encompass both primary data sets including 5632 compounds as well as 249 values from hit confirmation screening against the hTau based substrate and 151 IC<sub>50</sub> values from confirmed hits.</p> <p> </p> <p><strong>Methods of data generation</strong></p> <p><strong>Enzymatic assay of human HDAC6 with commercial peptide substrate. </strong></p> <p>The assay using the commercial peptide substrate (BOC-Gly-(Ac)Lys-aminoluciferin) was obtained from Promega Inc.. In the beginning the assay buffer is thawed and the lyophilized substrate is dissolved according to the technical manual (Promega Inc.) to create the substrate reagent. HDAC6 (obtained from BPS Biosciences) is dissolved in assay buffer at 0.2 nM, which is twice the final assay concentration. Compounds and controls are added to the plates using acoustic dispensing to reach a final concentration of 10 µM in the assay followed by 5 µl enzyme solution per well. Plates are centrifuged shortly and incubated for 10 min at RT. Afterwards, 5 µL/well substrate solution are added to the wells, centrifuged shortly and incubated for 10 min prior detection of the luminescence signal on a multimode reader. Primary screening was done at one concentration (10 µM) in singlicates.</p> <p> </p> <p><strong>Enzymatic assay of human HDAC6 with custom peptide substrate. </strong></p> <p>The assay was designed based on a commercial HDAC6 assay available from Promega Inc. This luminescence assay works by an aminoluciferin coupled HDAC6 peptide substrate. Upon deacetylation of the peptidic substrate by HDAC6 (obtained from BPS Biosciences) Trypsin (obtained from Sigma-Aldrich) can cleave the aminoluciferine from the peptide which can be converted by Luciferase (obtained from AAT Bioquest) to the detected signal. First, a twofold concentrated enzyme solution was generated, consisting of 4 nM HDAC6 and 0.1% BSA in HEPES buffer (25 mM HEPES, 137 mM NaCl, 2.7 mM KCl and 1 mM MgCl2, pH 7.0). Second, a twofold peptide solution was generated containing 100 µM custom made peptide (Boc-Ile-Asp-(Dimethyl)Lys-(Ac)Lys-aminoluciferin) in HEPES buffer. Compounds and controls are added to the plates using acoustic dispensing to reach a final concentration of 10 µM in the assay followed by 5 µl enzyme solution per well. Plates are centrifuged shortly and 5 µL/well peptide solution are added to the wells, centrifuged shortly and incubated for 30 min at RT. Afterwards, 5 µL detection reagent (0.067 mg/mL Luciferase, 133.3 µM ATP, 0.133 mg/mL Trypsin in HEPES buffer) were added to each well. Plates were centrifuged shortly and measured on a multimode reader after 30 min incubation at RT in the dark. Primary screening was done at one concentration (10 µM) in singlicates.</p> <p> </p> <p><strong>Hit confirmation of the active molecules of the enzymatic assay of human HDAC6 with custom peptide substrate</strong></p> <p>The assay was designed based on a commercial HDAC6 assay available from Promega Inc. This luminescence assay works by an aminoluciferin coupled HDAC6 peptide substrate. Upon deacetylation of the peptidic substrate by HDAC6 (obtained from BPS Biosciences) Trypsin (obtained from Sigma-Aldrich) can cleave the aminoluciferine from the peptide which can be converted by Luciferase (obtained from AAT Bioquest) to the detected signal. First, a twofold concentrated enzyme solution was generated, consisting of 4 nM HDAC6 and 0.1% BSA in HEPES buffer (25 mM HEPES, 137 mM NaCl, 2.7 mM KCl and 1 mM MgCl2, pH 7.0). Second, a twofold peptide solution was generated containing 100 µM custom made peptide (Boc-Ile-Asp-(Dimethyl)Lys-(Ac)Lys-aminoluciferin) in HEPES buffer. Compounds and controls are added to the plates using acoustic dispensing to reach a final concentration of 10 µM in the assay followed by 5 µl enzyme solution per well. Plates are centrifuged shortly and 5 µL/well peptide solution are added to the wells, centrifuged shortly and incubated for 30 min at RT. Afterwards, 5 µL detection reagent (0.067 mg/mL Luciferase, 133.3 µM ATP, 0.133 mg/mL Trypsin in HEPES buffer) were added to each well. Plates were centrifuged shortly and measured on a multimode reader after 30 min incubation at RT in the dark. Hit confirmation was done at one concentration (10 µM) in triplicates.</p> <p> </p> <p><strong>Determination of IC50 values for inhibition of enzymatic assay of human HDAC6 with custom peptide substrate</strong></p> <p>The assay was designed based on a commercial HDAC6 assay available from Promega Inc. This luminescence assay works by an aminoluciferin coupled HDAC6 peptide substrate. Upon deacetylation of the peptidic substrate by HDAC6 (obtained from BPS Biosciences) Trypsin (obtained from Sigma-Aldrich) can cleave the aminoluciferine from the peptide which can be converted by Luciferase (obtained from AAT Bioquest) to the detected signal. First, a twofold concentrated enzyme solution was generated, consisting of 4 nM HDAC6 and 0.1% BSA in HEPES buffer (25 mM HEPES, 137 mM NaCl, 2.7 mM KCl and 1 mM MgCl2, pH 7.0). Second, a twofold peptide solution was generated containing 100 µM custom made peptide (Boc-Ile-Asp-(Dimethyl)Lys-(Ac)Lys-aminoluciferin) in HEPES buffer. Compounds and controls are added to the plates using acoustic dispensing to reach a final concentration of 10 µM in the assay followed by 5 µl enzyme solution per well. Plates are centrifuged shortly and 5 µL/well peptide solution are added to the wells, centrifuged shortly and incubated for 30 min at RT. Afterwards, 5 µL detection reagent (0.067 mg/mL Luciferase, 133.3 µM ATP, 0.133 mg/mL Trypsin in HEPES buffer) were added to each well. Plates were centrifuged shortly and measured on a multimode reader after 30 min incubation at RT in the dark. IC50 values were determined using 7 point dose response curves (DRCs) between 20 µM and 312 nM. In case inhibition values were not below 50% additional 7 point DRCs were measured, starting at 312 nm with a dilution factor of 2. All DRCs were recorded in triplicates.</p>
Regulatory spine RS3 residue of protein kinases: a lipophilic bystander or a decisive element in the small-molecule kinase inhibitor binding?
<p>Datasets related to publication: </p> <p>Shevchenko E, Pantsar T: Regulatory spine RS3 residue of protein kinases: a lipophilic bystander or a decisive element in the small-molecule kinase inhibitor binding?. <em><em>Biochem Soc Trans</em></em> 28 February 2022; 50 (1): 633–648</p> <p>https://doi.org/10.1042/bst20210837</p> <p> </p> <p> </p>
Candidate compounds from the design of covalent Bruton's tyrosine kinase (BTK) inhibitors via focused deep generative modeling
<pre>A total of 1491 candidate inhibitors for covalent inhibition of BTK are deposited as SMILES strings together with 34 known covalent BTK inhibitors used to guide generative computational design. The study will be reported in a publication in Molecules under the authors' names.</pre>
Risk of bias assessments and support for judgement with ROB 2 tool for the Cochrane Review: Janus kinase inhibitors for the treatment of COVID-19
<p>Risk of bias assessments and support for judgement with ROB 2 tool for the Cochrane Review: Janus kinase inhibitors for the treatment of COVID-19.</p>
The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor-resistant ER+ breast cancer with mitotic aberrations
<p>This study aims to investigate the accumulation of genomic instability and chromosome segregation errors after the acquisition of resistance to CDK4/6i in ER+ breast cancer and to test the efficacy of mitotic kinase inhibitors as a potential treatment for CDK4/6i-resistant breast cancer patients.</p> <p><strong>This repository contains whole-exome and shallow whole-genome sequencing from luminal breast cancer cell lines (T47D, LY2, MDA-MB-361, CAMA1, MCF7, KPL1, ZR751, HCC1428) both at the untreated or Parental state and post resistance to Palbociclib.</strong></p> <p>Palbociclib resistance was developed by continuous dose-escalation of palbociclib up to 0.5-1 μM until cell growth was observed in the presence of the drug (6-8 months for cell lines). During this time, parental cell lines and organoids were cultured in regular media to match the time spent in culture. Once resistance was established, Palbo-R cell lines were cultured in a regular growth medium without palbociclib. Cells were cultured without palbociclib for at least two weeks before evaluating resistance.</p>
Selectivity profiling of multi-kinase inhibitors across the Human Kinome from ChEMBL
<p>Reported is the list of 596 protein kinase pairs, consisting of 141 kinases and selectivity profiles of 10,060 multi-kinase inhibitors found in ChEMBL23 high-confidence data. For each of the reported protein kinase pairs, UniProt IDs defining the kinase forming a pair is provided, as well as the shared inhibitors and their selectivity profiles. For each target within the pair, potency value for each compound is reported as pIC50 value, as well as the absolute potency difference used to assess the selectivity profiles.</p>
PubChem Data Mining of OXPHOS inhibitors: scripts, data, and models
<p>README doc, source, and data files from PubChem data mining project to identify OXPHOS inhibitory chemotypes.</p>
Ir and NMR for article Synthesis and Biological Activity Evaluation of New Isatin-Gallate Hybrids as Antioxidant and Anticancer Agents (in vitro) and In-silico Study as Anticancer Agents and Coronavirus Inhibitors
<p>this is IR and NMR data for article titled <strong>Synthesis and Biological Activity Evaluation of New Isatin-Gallate Hybrids as Antioxidant and Anticancer Agents (<em>in vitro</em>) and In-silico Study as Anticancer Agents and Coronavirus Inhibitors </strong></p> <p> </p>
Figure 1 in Glufosinate enhances the activity of protoporphyrinogen oxidase inhibitors
Figure 1. Glufosinate reshapes the levels of amino acids in Amaranthus palmeri. Levels of glutamine, glutamate, proline, and arginine in untreated (gray) and glufosinate-treated (blue) plants at 24 h after treatment (A). Levels of glutamate over time in untreated (gray) and glufosinate-treated (blue) plants (B). Asterisks (*) indicate means are significantly different by t-test (P <0.05) between untreated and glufosinate-treated within each amino acid or time point. Error bars represent the standard deviations of the means.
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Allen Brain Atlas
Allen Brain Atlas is an Allen Institute collection of brain map atlases, datasets, APIs, and analysis tools covering mouse, human, and non-human primate brain resources.
Annotated Behaviour and Observability Dataset (ABODe)
ABODe is a University of Edinburgh DataShare dataset for behavior classification in group-housed mice using home-cage video, identities, bounding boxes, ground-plate positions, and annotator labels.
DANDI Archive for NWB datasets
DANDI is a BRAIN Initiative archive for publishing and sharing neurophysiology data, including electrophysiology, optophysiology, and behavioral data packaged as NWB and related standards.
International Brain Laboratory public data
The International Brain Laboratory public data releases expose standardized mouse decision-making experiments, including Neuropixels recordings, widefield calcium imaging, behavior, and session metadata accessed through the ONE API.
OpenNeuro
OpenNeuro is a free, open platform for sharing neuroimaging datasets, with public search, dataset pages, and download paths for web, S3, DataLad, and the OpenNeuro CLI.