methotrexate   Click here for help

GtoPdb Ligand ID: 4815

Synonyms: Abitrexate® | amethopterin | Nordimet® | Rasuvo®
Approved drug PDB Ligand Immunopharmacology Ligand
methotrexate is an approved drug (FDA (1953), EMA (2016))
Compound class: Synthetic organic
Comment: Methotrexate is a folate (folic acid) analogue that is classified as an antimetabolite and antifolate drug, and a disease-modifying anti-rheumatic drug (DMARD). It is used clinically for its antiproliferative and anti-inflammatory effects. The primary action of methotrexate is inhibition of the enzyme dihydrofolate reductase (DHFR). DHFR is essential for the production of precursors that are required for de novo purine synthesis.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species

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2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 13
Hydrogen bond donors 5
Rotatable bonds 10
Topological polar surface area 210.54
Molecular weight 454.17
XLogP -2.67
No. Lipinski's rules broken 1
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES OC(=O)CCC(C(=O)O)NC(=O)c1ccc(cc1)N(Cc1cnc2c(n1)c(N)nc(n2)N)C
Isomeric SMILES OC(=O)CC[C@@H](C(=O)O)NC(=O)c1ccc(cc1)N(Cc1cnc2c(n1)c(N)nc(n2)N)C
InChI InChI=1S/C20H22N8O5/c1-28(9-11-8-23-17-15(24-11)16(21)26-20(22)27-17)12-4-2-10(3-5-12)18(31)25-13(19(32)33)6-7-14(29)30/h2-5,8,13H,6-7,9H2,1H3,(H,25,31)(H,29,30)(H,32,33)(H4,21,22,23,26,27)/t13-/m0/s1
InChI Key FBOZXECLQNJBKD-ZDUSSCGKSA-N
Immunopharmacology Comments
Methotrexate is a DMARD prescribed for rheumatoid arthritis, psoriatic arthritis and vasculitis. In inflammation its mode of action relates to its ability to inhibit folate pathway enzymes, including aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC; P31939). In vivo conversion of methotrexate to methotrexate-polyglutamates is required for ATIC inhibition [2]. ATIC inhibition leads to intracellular accumulation of its substrate aminoimidazole carboxamide adenosine ribonucleotide (AICAR), increased adenosine release and modulation of immune cell (neutrophils, natural killer cells, monocytes/macrophages and T cells) function, effects which ultimately produce a potent anti-inflammatory effect [1,4]. Key inflammatory mediators such as IL-17, IL-22, IL-23 and CCL20 are downregulated by methotrexate.

Low-dose methotrexate was evaluated to determine if inflammation inhibition could provide an effective approach for the secondary prevention of atherosclerotic events (heart attack, stroke, and cardiovascular death) in the phase 3 Cardiovascular Inflammation Reduction Trial (CIRT; NCT01594333) [3]. Analysis of results from CIRT concluded that methotrexate was no more effective than placebo in patients with stable atherosclerosis; it did not reduce the number of cardiovascular events, or reduce inflammation markers such as IL-1β, IL-6 and C-reactive protein, relative to placebo-treated controls [6].
Immunopharmacology Disease
Disease X-Refs Comment References
Vasculitis Disease Ontology: DOID:865
 Approved drug for vasculitis.
Rheumatoid arthritis Disease Ontology: DOID:7148
OMIM: 180300
 Approved drug for RA.
Psoriatic arthritis Disease Ontology: DOID:9008
 Approved drug for PsA.
Juvenile idiopathic arthritis Oral solution of methotrexate approved for JIA in pediatric pateints.
Immunopaedia Case Studies Links
My eyes cross at twilight
14 year old with severe hip pain
A 7 year old with severe muscle weakness and difficulty walking
A case of scaly annular plaques
Case of eye injury and decreased vision