The ChEMBL_18 release includes the following new datasets:
University of Vienna G-glycoprotein (pgp) screening data
UCSF MMV Malaria Box screening data
DNDi Trypanosoma cruzi screening data
DrugMatrix in vivo toxicology data
In addition, 43,335 new compound records from 2015 publications in the primary literature have been added to this release. Approved drug and usan data have also been updated, with 103 new structures added.
Updates to the protein family classification
A review and update of the ChEMBL protein family classification has been carried out. The main changes are listed below:
New ion channel/transporter classification, based on the BPS classification
New epigenetic protein classification, based on SGC/ChromoHub classification
Modification of kinase classification, to follow Human Kinome classification
Assay classification and ontology mapping
The following annotations and classifications have been added to the ChEMBL assay data:
Classification of assay format (e.g., biochemical, cell-based, organism-based) using BioAssay Ontology
Classification of endpoints (e.g., IC50, AUC, Ki) using BioAssay Ontology
Addition of Physicochemical and Toxicity assay type classification
Mapping of assay cell-lines to CLO, EFO and Cellosaurus
Mapping of standard units to Unit Ontology and QUDT
Capture of assay parameters
A new table in the database (assay_parameters), is used to capture additional properties of assays such as dose, administration route, time points. These additional parameters are displayed on the Assay Report Card.
Target predictions
Bioactivity data for single protein targets in ChEMBL have been used to train and validate two Naive Bayesian multi-label classifier models (at <= 1uM and <= 10uM bioactivity cutoffs respectively). These models have been subsequently employed to predict biological targets for a set of approved drugs, which are displayed on in the new Target Predictions section of the Compound Report Card, where applicable. Since some of the predictions correspond to compound/target pairs that were included in the training set for the models, these are shown in white, to distinguish them from genuine predictions (coloured light yellow). Only predictions scoring >= 0.2 are included in the result tables. The models were built with open source tools such as RDKit and scikit-learn and are available upon request.
We would appreciate any feedback on this feature, and any further ideas you may have on including predicted data on top of ChEMBL experimental data.
UniChem connectivity mapping
In addition to the standard UniChem cross-references shown on the report card (based on exact InChI Key matching), a new link is included to an expanded view of UniChem cross-references, generated based on InChI connectivity layer matching (e.g.,
This expanded view shows any compounds in UniChem that share the same connectivity as the query structure, even if they have stereochemical, isotopic or protonation state differences. The differences between the query and retrieved structures are shown by their position in the table: the first column shows compounds that match in all InChI layers, while the subsequent columns show those structures that differ in stereochemistry (s column), isotope (i column), protonation state (p column), or various combinations of these layers (final four columns). A button at the top of the table gives the additional option to retrieve compounds that match individual components of a mixture or salt. Where the query structure consists of multiple components, matches to each of these components will be coloured different colours (e.g., black, blue, red).
ChEMBL RDF Update
The ChEMBL RDF data model has been enhanced and now includes the following information:
Drug mechanism of action and binding site information
Molecule hierarchy
Target relationships
Assay format
Cell-line information
More information (documentation, SPARQL endpoint and example queries), about the RDF version of the ChEMBL database can be found on the EBI-RDF Platform and you can download the RDF files from the ChEMBL ftpsite.
Web Service Update
Three new Web Service calls focused on approved drugs, mechanism of action and compound forms are now available. Example calls to these methods can be seen below and also please visit the ChEMBL Web Service page for more details.
I've missed quite a few rhodopsin-like GPCR structures, so catching up on some of this today. Below are representative structures of all the 22 sequence distinct rhodopsin-like GPCRs which are in the public domain as of today. I've done an initial alignment, and the areas the ambiguities are in, are variable between structures, and also within structure sets (same sequence, different ligand, cell, etc). It is incredible that there are now 22 of these, and of course, representative structures of some of the other GPCR superfamilies too.
On April 30th 2014 the University of Strathclyde will host a seminar on Allosteric Drug Design organised by the smsdrug.net collaboration. The goal of the seminar is to bring together academic and industrial researchers with an interest in allosteric drug design and development with a view to identifying future collaborative and funding opportunities.
The seminar consists of a series of three talks by : Dr. Gerard JP van Westen (EMBL-EBI ; ChEMBL), Prof. Dr. Leonardo Scapozza (University of Geneva) and Dr. Laurent Galibert (Alpine Institute for Drug Discovery). The talks will cover various of drug design in relation to allosteric drug targets. Talks are aimed at a broad audience.
On February 18th the FDA approved Droxidopa (tarde name Northera™) for the treatment of neurogenic orthostatic hypotension (NOH). NOH is a rare, chronic and often debilitating drop in blood pressure upon standing, and is associated with Parkinson's disease, multiple-system atrophy, and pure autonomic failure. Symptoms of NOH include dizziness, light-headedness, blurred vision, fatigue and fainting when a person stands.
Target(s)
Droxidopa (also known as L-DOPS, L-threo-dihydroxyphenylserine, and SM-5688) is a prodrug which can be converted to norepinephrine (noradrenaline) by Aromatic L-amino acid decarboxylase (Uniprot P20711 ; EC 4.1.1.28). Norepinephrine in turn can be converted to epinephrine by Phenylethanolamine N-methyltransferase ( Uniprot P11086 ). Droxidopa can cross the blood brain barrier, contrary to epinephrine and norepinephrine. Patients with NOH suffer from depleted levels of epinephrine and norepinephrine. Droxidopa increases the levels of both in the peripheral nervous system and leads to an increased heart rate and blood pressure.
Droxidopa (CHEMBL2103827; Pubchem : 92974 ) is a small molecule drug with a molecular weight of 213.2 Da, an AlogP of -2.92, 3 rotatable bonds, and no rule of 5 violations.
Droxidopa starting dose is 100mg three times daily (which can be titrated to a maximum of 600 mg three times daily). One dose should be taken in late afternoon at least 3 hours prior to bedtime to reduce the potential for supine hypertension during sleep.
Warnings
Neuroleptic malignant syndrome (NMS) has been reported with Droxidopa use during post-marketing surveillance in Japan. NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia, muscle rigidity, involuntary movements, altered consciousness, and mental status changes.
Ischemic Heart Disease, Arrhythmias, and Congestive Heart Failure
Droxidopa may exacerbate existing ischemic heart disease, arrhythmias and congestive heart failure.
Pharmacokinetics
Absorption
Cmax of droxidopa were reached by 1 - 4 hours post-dose in healthy volunteers. High-fat meals have a moderate impact on droxidopa exposure with Cmax and AUC decreasing by 35% and 20% respectively, and delaying Cmax by approximately 2 hours.
Distribution
Droxidopa exhibits plasma protein binding of 75% at 100 ng/mL and 26% at 10,000 ng/mL with an apparent volume of distribution of about 200 L.
Metabolism
The metabolism of droxidopa is mediated by catecholamine pathway and not through the cytochrome P450 system. Plasma norepinephrine levels peak within 3 to 4 hours (generally < 1 ng/mL) and variable with no consistent relationship with dose. The contribution of the metabolites of droxidopa other than norepinephrine to its pharmacological effects is not well understood.
Elimination
The mean elimination half-life of droxidopa is 2.5 hours. The major route of elimination of droxidopa and its metabolites is via the kidneys.
Drug Interactions
No dedicated drug-drug interaction studies were performed for droxidopa. Carbidopa, a peripheral dopa-decarboxylase inhibitor, could prevent the conversion of droxidopa to norepinephrine outside of the central nervous system (CNS).
L-DOPA/dopa-decarboxylase inhibitor combination drugs decreased clearance of droxidopa, increased AUC to droxidopa approximately 100%, and increased exposure to 3-OM-DOPS of approximately 50%. However, it was found that the decreased clearance was not associated with a significant need for a different treatment dose or increases in associated adverse events.
Dopamine agonists, amantadine derivatives, and MAO-B inhibitors do not appear to effect droxidopa clearance, no dose adjustments are required.
Pregnancy
Droxidopa is classified as pregnancy category C. There are no adequate and well controlled trials in pregnant women. The license holder is Chelsea Therapeutics, the prescribing information can be found here.
On December 18, 2013, the FDA approved Anoro Ellipta for the once-daily, long-term maintenance treatment of airflow obstruction in patients with obstructive pulmonary disease (COPD). Anoro is a combination of umeclidinium (62.5 mcg - more details below) and vilanterol inhalation powder (25 mcg - already approved in a different formulation). Ellipta is the single inhaler device:
The majority of COPD cases are due to cigarette smoking and this lung disease is a leading cause of death in the United States. Patients affected by COPD experience breathing difficulties worsening with the time as well as chronic cough and chest tightness.
Umeclidinium
Umeclidinium (also known as umeclidinium bromide, GSK573719A and GSK573719) is a small molecule with a molecular weight of 428.6 Da and AlogP of 3.34, 8 rotatable bounds and no Lipinski's rule of five violation.
Molecular formula: C29H34NO2
Canonical SMILES: OC(c1ccccc1)(c2ccccc2)C34CC[N+](CCOCc5ccccc5)(CC3)CC4
Standard InChI: InChI=1S/C29H34NO2/c31-29(26-12-6-2-7-13-26,27-14-8-3-9-15-27)28-16-19-30(20-17-28,21-18-28)22-23-32-24-25-10-4-1-5-11-25/h1-15,31H,16-24H2/q+1
Alternate form of the molecule in ChEMBL: CHEMBL523299
Mechanism of action
Anoro Ellipta relaxes the muscles located around the airways of the lung to increase the airflow in patients. This mechanism of action is mediated via umeclidinium, anticholinergic stopping muscle tightening in combination with vilanterol, a long-acting beta2-adrenergic agonist (LABA).
Safety information
The phase III trials for Anoro Ellipta included seven clinical studies, involving around 6,000 patients with COPD. The mainly reported side-effect were narrowing and obstruction of the respiratory airway (paradoxical bronchospasm), cardiovascular effects, increased pressure in the eyes (acute narrow-angle glaucoma), and worsening of urinary retention.
Note that Anoro Ellipta is not indicated for the treatment of asthma and displays a boxed warning for this indication.
Anoro Ellipta is manufactured by GlaxoSmithKline, Research Triangle Park, N.C.
On February 14, 2014, the FDA approved elosulfase alfa for the treatment of Mucopolysaccharidosis Type IVA (Morquio A syndrome). Elosulfase alfa is intended to replace the missing GALNS enzyme involved in an important metabolic pathway. Absence of this enzyme leads to problems with bone development, growth and mobility.
Mucopolysaccharidoses comprise a group of lysosomal storage disorders caused by the deficiency of
specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). Mucopolysaccharidosis IVA (MPS IVA, Morquio A Syndrome) is characterized by the absence or marked reduction in N-acetylgalactosamine-6-sulfatase activity. The sulfatase activity deficiency resultsin the accumulation of the GAG substrates, KS and C6S, in the lysosomal compartment of cells throughout the body. The accumulation leads to widespread cellular, tissue, and organ dysfunction. It is a rare autosomal recessive disease, affecting approximately 800 people in the US, and significantly shortens life expectancy, with most patients dying at an early age. Sulfonase alfa is the first approved treatment for Morquio A syndrome.
Elosulfase alfa is intended to provide the exogenous enzyme N-acetylgalactosamine-6-sulfatase that will be taken up into the lysosomes and increase the catabolism of the GAGs KS and C6S. Elosulfase alfa uptake by cells into lysosomes is mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of elosulfase alfa to mannose-6-phosphate receptors.
Elosulfase alfa is a soluble glycosylated dimeric protein with two oligosaccharide chains per monomer. Each monomeric peptide chain contains 496 amino acids and has an approximate molecular mass of 55 kDa (59 kDa including the oligosaccharides). One of the oligosaccharide chains contains bis-mannose 6-phosphate (bisM6P). bisM6P binds a receptor at the cell surface and the binding mediates cellular uptake of the protein to the lysosome.
The recommended dose is 2mg per kg given intravenously over a minimum range of 3.5 to 4.5 hours, based on infusion volume, once every week. Pre-treatment with antihistamines with or without antipyretics is recommended 30 to 60 minutes prior to the start of the infusion. The mean AUC0-t at first administration is 238 min x μg/mL, but increases to 577 by week 22 of treatment, likely due to the development of neutralising antibodies. The mean elimination half-life likewise was measured as 7.52 min at first dosage, and 35.9 min at week 22 of treatment.
Elosulfase alfa comes with a boxed warning for potentially life-threatening anaphylactic reactions in some patients.
The license holder for Vimizim™is BioMarin, and the full prescribing information can be found here.
Non-24-hour sleep–wake disorder (Non-24) is a chronic circadian rhythm sleep disorder, mostly affecting blind people. It is characterised by insomnia or excessive sleepiness related to abnormal synchronization between the 24-hour light–dark cycle and the endogenous circadian cycle (slightly longer than 24 hours). This deviation can be corrected by exposure to solar light, which resets the internal clock, however, the loss of photic input, and the absence of light perception in the majority of patients, prevents them from drifting back into normal alignment.
Tasimelteon is an agonist at melatonin MT1 and MT2 receptors, with a relative greater affinity for MT2. These receptors are thought to be involved in the control of circadian rhythms, consequently, the binding of tasimelteon to these receptors, and the resulting induced somnolence, is believed to be the mechanism by which tasimelteon aids in the synchronisation of the internal circadian clock with the 24-hour light–dark cycle.
Melatonin receptors (Uniprot accession: P48039 and P49286; ChEMBL ID: CHEMBL2094268) are members of the G-protein coupled receptor 1 family. There are no known 3D structures for these particular proteins though, however there are now several relevant homologous structures of other members of the family (see here for a current list of representative rhodopsin-like GPCR structures).
The -melteon USAN/INN stem covers selective melatonin receptor agonists. Tasimelteon is the second approved agent in this class, following the approval of Takeda's Ramelteon in 2005. Contrary to its predecessor, tasimelteon is not currently indicated to treat insomnia, and has received orphan-product designation by the FDA. Agomelatine is another member of this class, but only approved in Europe (PMID: 18673165).
Tasimelteon (IUPAC Name: N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl]propanamide; Canonical smiles: CCC(=O)NC[C@@H]1C[C@H]1c2cccc3OCCc23; ChEMBL: CHEMBL2103822; PubChem: 10220503; ChemSpider: 8395995; Standard InChI Key: PTOIAAWZLUQTIO-GXFFZTMASA-N) is a synthetic small molecule , with a molecular weight of 245.3 Da, 2 hydrogen bond acceptors, 1 hydrogen bond donor, and has an ALogP of 2.2. The compound is therefore fully compliant with the rule of five.
Tasimelteon is available as oral capsules and the recommended daily dose is one single capsule of 20 mg, taken before bedtime, at the same time every night. The peak concentration (Cmax) is reached at 0.5 to 3 hours after fasted oral administration, and at steady-state in young healthy subjects, the apparent oral volume of distribution (Vd/F) is approximately 56-126 L. Tasimelteon should not be administered with food, since food decreases its bioavailability, lowering the Cmax by 44%, and delaying the Tmax by approximately 1.75 hours. At therapeutic concentrations, tasimelteon is strongly bound to plasma proteins (90%).
The primary enzymatic systems involved in the biotransformation of tasimelteon in the liver are CYP1A2 and CYP3A4. Therefore, co-administration of tasimelteon with inhibitors of CYP1A2 and CYP3A4 or inducers of CYP3A4 may significantly alter the plasma concentration of tasimelteon. Metabolism of tasimelteon consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. Phenolic glucuronidation is the major phase II metabolic route. Following oral administration of radiolabeled tasimelteon, 80% of total radioactivity is excreted in urine and approximately 4% in feces. The mean elimination half-life (t1/2) for tasimelteon is 1.3 ± 0.4 hours.
The license holder for HetliozTM is Vanda Pharmaceuticals, and the full prescribing information can be found here.
We have just had this editorial published in Future Medicinal Chemistry. It is a high-level overview of ChEMBL, SureChEMBL and related resources, aimed primarily at medicinal chemists. The Open Access paper is here.
%T The ChEMBL database: a taster for medicinal chemists
%J Future Medicinal Chemistry
%D 2014
%O DOI:10.4155/fmc.14.8
%A G. Papadatos
%A J.P. Overington
Droxidopa (CHEMBL2103827; Pubchem : 92974 ) is a small molecule drug with a molecular weight of 213.2 Da, an AlogP of -2.92, 3 rotatable bonds, and no rule of 5 violations.
The majority of COPD cases are due to cigarette smoking and this lung disease is a leading cause of death in the United States. Patients affected by COPD experience breathing difficulties worsening with the time as well as chronic cough and chest tightness.
We have just had this editorial published in Future Medicinal Chemistry. It is a high-level overview of ChEMBL, SureChEMBL and related resources, aimed primarily at medicinal chemists. The Open Access paper is here.
