[IFM] LABORATOIRE D’INGÉNIERIE DES FONCTIONS MOLÉCULAIRES

GRALL

What: the Glycine Receptor Allosteric Ligand Library (GRALL) is the first database of allosteric modulators of a human synaptic receptor with a structural annotation based on their binding site on the receptor. GRALL offers a collection of 218 chemical entities with documented modulatory activities at homomeric glycine receptors (GlyR) α1 and α3, which includes agonists, antagonists, positive and negative allosteric modulators and large number of experimentally inactive compounds. The GRALL database provides an extensive overview of the pharmacology of a relevant drug target that is expected to boost the development of in silico methodologies for allosteric drug design.

Why: GRALL is a unique contribution to the field of neuropharmacology. This collection provides information on the chemical structure, the direction of modulation, the potency, the 3D molecular structure and quantum-mechanical charges of a large number of biologically active compounds at a human synaptic receptor. Most importantly, a large fraction of modulators in GRALL comes with a structural annotation of their ligand-binding site on the receptor, which was assigned using a level of confidence from 1 (highest) to 5 (lowest) depending on the quality of the evidence supporting the annotation. This information, which is currently missing in popular drug banks like ChEMBL, PubChem, or Binding DB provides a stringent benchmark that is expected to boost the development of predictive in silico strategies for allosteric drug design. Moreover, it can be used to combine ligand-based and structure-based approaches for drug design.

How: GRALL is organized as a web-accessible database, where compounds can be ranked by name, SMILES, chemical family, annotated binding site, level of confidence of annotation, the direction of modulation, the activity type and value. To extract information, the database can be searched using keywords (see below), or downloaded in the CSV format. For each entry, the database allows for immediate visualization of the 2D chemical structure and provides the DOI of the most relevant publication associated to it. The hyperlink in the last column provides access to the 3D representation in MOL2 format, which is suitable for straightforward visualization. The whole chemical library can also be directly downloaded in a multi MOL2 format for direct docking or virtual screening.

Contact: Dr. Marco Cecchini (mcecchini@unistra.fr)

Reference: Cerdan A.H., Sisquellas M., Pereira G., Gomes D.E.B., Changeux J-P. & Cecchini M. “The glycine receptor allosteric ligands library (GRALL)”. Bioinformatics 36, 3379–3384 (2020). https://doi.org/10.1093/bioinformatics/btaa170

Download:       CSV       MOL2

Annotation:

  • Chemical family: alcohol, alkaloid, aminoacid, avermectin, bilabolide, cannabinoid, cyanotriphenylborate, dihydropyridine, general_anesthetic, ginkgolic-acid, ginkgolide, glucocortico_steroid, glutamate, HTS, neurosteroid, phenylalanine, phenylpyrazole, picrotoxin, propofol, sulfonamide, tropeine.
  • Binding site: (+)-neurosteroid, (−)-neurosteroid, (LA)-tropeine, alcohol, ivermectin, orthosteric, pore, top_ECD or N.A.

  • Effect:
    0: Inactive
    +: Agonism or positive modulation
    −: Antagonism or negative modulation
    N.A.: Not Available
  • Activity type: EC50, IC50, Kd, Maximum_effect(%),Mean_potentiation(%) or N.A.
  • Level of confidence:
    1: High-Resolution Structure from GlyR
    2: High-Resolution Structure from other pLGIC + concordant evidence in GlyR
    3: Site-Directed Mutagenesis
    4: Modelling / Computational Studies
    5: Structural Similarities with annotated ligands
    N.A: Not Available

Update: We encourage researchers to contact us and submit missing or new molecules via the preformatted form (Submit new ligand). Upon verification, the transmitted information will be added to the database and published online.

 

Acknowledgments:

 

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