Ion Channel Focused Library (Fingerprint Similarity)

Ion channels, membrane transport proteins expressed in almost all living cells, are among the most important therapeutic drug targets for treating a number of different pathophysiologies. Historically, however, the development of drugs targeting this protein class has been difficult. Several challenges associated with small molecule drug discovery include the validation of new ion channel targets and the identification of acceptable medicinal chemistry leads. Despite some important drugs in clinical use today, as a class, ion channels remain underexploited in drug discovery, and many existing drugs are poorly selective with significant toxicities or suboptimal efficacy.

Life Chemicals has applied several tools to predict ion channel modulators among compounds in its HTS Compound Collection to design this Ion Channel Compound Library of over 5,000 structurally diverse screening compounds (Fig. 1). The compound collection is aimed at contributing to high throughput screening (HTS) and high content screening (HCS) in ion channel drug discovery.

IInitially, almost 19,000 referent compounds with reported ion channel blocking activity were obtained from the ChEMBL database. Only compounds with moderate and high activity against ion channels were kept. Then a similarity search of the reference set has been performed against Life Chemicals HTS Compound Collection employing 2D molecular fingerprints and two similarity metrics (Tanimoto > 0.85 and Tversky > 0.85). The resulting compound set was filtered by Lipinski's Rule of Five to keep only drug-like screening compounds. PAINS and molecules with "bad" and reactive groups have been filtered out.

  • Vanilloid receptor
  • HERG
  • Acetylcholine receptor; alpha1/beta1/delta/gamma
  • Annexin A2/S100-A10
  • Anoctamin-1
  • Apoptosis regulator Bcl-2
  • Calcium-activated potassium channel alpha-1 subunit
  • Cholesteryl ester transfer protein
  • Cystic fibrosis transmembrane conductance regulator
  • GABA-A receptor; alpha-3/beta-3/gamma-2
  • GABA-A receptor; anion channel
  • Glutamate NMDA receptor subunits 3A/epsilon 2/GRIN1/GRIN2B
  • Glutamate receptor ionotropic, AMPA 2/AMPA 4
  • Kir3.1/Kir3.4
  • MCOLN3 protein
  • Neuronal acetylcholine receptor protein alpha-4, alpha-7, alpha3/beta4, alpha4/beta2  subunits
  • P2X, P2X purinoceptor 3, P2X purinoceptor 7
  • Perforin-1
  • Potassium channel subfamily K member 3
  • Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 and 4
  • Presenilin er Ca2+ leak channel
  • Serotonin 3 (5-HT3) receptor
  • Serotonin 3a (5-HT3a) receptor
  • Short transient receptor potential channel 6
  • Sodium channel alpha subunits; brain (types I, II, III)
  • Sodium channel protein types I, II, V, IX, X alpha subunits
  • Sodium/potassium-transporting ATPase
  • Sulfonylurea receptor 1, Kir6.2
  • Transient receptor potential cation channel subfamily A member 1
  • Transient receptor potential cation channel subfamily M member 8
  • Transient receptor potential cation channel subfamily V member 4
  • Voltage-gated L-type calcium channel
  • Voltage-gated L-type calcium channel alpha-1C subunit
  • Voltage-gated L-type calcium channel alpha-1D subunit
  • Voltage-gated N-type calcium channel alpha-1B subunit
  • Voltage-gated N-type calcium channel alpha-1B subunit/Amyloid beta A4 precursor protein-binding family A member 1
  • Voltage-gated potassium channel subunit Kv1.3
  • Voltage-gated potassium channel subunit Kv1.5
  • Voltage-gated potassium channel subunit Kv7.1
  • Voltage-gated potassium channel subunit Kv7.2
  • Voltage-gated potassium channel subunit Kv7.4
  • Voltage-gated potassium channel, IKs; KCNQ1(Kv7.1)/KCNE1(MinK)
  • Voltage-gated T-type calcium channel alpha-1G subunit
  • Voltage-gated T-type calcium channel alpha-1H subunit
  • Voltage-gated T-type calcium channel alpha-1I subunit

Representative compounds from the Life Chemicals Ion Channel Focused Library.

Fig 1. Potential ion channel blockers from the Life Chemicals Ion Channel Focused Library (Fingerprint Similarity).

 

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