Helicase Focused Library

Helicases are ATP driven molecular motor proteins that catalyze unwinding of the duplex polynucleotides to provide two separate nucleic acid strands for replication, transcription, and recombination. These enzymes are present in all organisms from viruses and bacteria to mammals and are required for replication and/or repair of their respective genomes. Thus Helicases are an interesting therapeutic target class, being pursued for both infectious diseases and cancer.

To design the Helicase Focused Library, Life Chemicals HTS Compound Collection was screened for compounds similar to those having helicase activity and available from ChEMBL, PubChem, DrugBank and scientific literature using MDL public keys and Tanimoto similarity cut-off of 84 %.

The reference database of 2,745 biologically active compounds from 9 helicase assays  representing the following helicase targets was compiled using the data available from patents and literature publications (Document IDs in the ChEMBL DB: CHEMBL3822370, CHEMBL4014334, CHEMBL1134109, CHEMBL1201862, CHEMBL1145280, CHEMBL1148307, CHEMBL1139458, CHEMBL4049423, CHEMBL1138995):

  • Probable global transcription activator SNF2L2 (helicase activity)
  • Transcription activator BRG1 (helicase activity)
  • Hepatitis C virus NS3 protease/helicase
  • Replicative DNA helicase
  • ATP-dependent DNA helicase Q1
  • Werner syndrome ATP-dependent helicase
  • Bloom syndrome protein (ATP-dependent DNA helicase)
  • Replication protein E1 (ATP-dependent DNA helicase)
  • Eukaryotic initiation factor 4A-III (ATP-dependent RNA helicase)

2,472 similar compounds resulting from the screen became the Life Chemicals Helicase Focused Library, with the most active compounds placed at the top of the list. Ro5 compliance is indicated; PAINS, toxic and reactive compounds are excluded from the library.

References:

  1. Lim SK, Othman R, Yusof R, Heh CH. Rational Drug Discovery of HCV Helicase Inhibitor: Improved Docking Accuracy with Multiple Seeding in AutoDock Vina and In Situ Minimization // Curr Comput Aided Drug Des. 2017;13(2):160-169.
  2. Simon NE, Schwacha A. The Mcm2-7 replicative helicase: a promising chemotherapeutic target // Biomed Res Int. 2014;2014:549719.
  3. Datta A, Brosh RM Jr. New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy // Front Mol Biosci. 2018;5:59.
  4. Shadrick WR, Ndjomou J, Kolli R, Mukherjee S, Hanson AM, Frick DN. Discovering new medicines targeting helicases: challenges and recent progress // J Biomol Screen. 2013;18(7):761-81.