DNA and RNA Polymerase Screening Libraries

Polymerases are enzymes crucial for the synthesis of nucleic acid polymers. Polymerases act in DNA metabolism, modulating different processes like mitosis, damage repair, transcription, and replication [1]. Therefore, the family of these crucial proteins can be a valuable target for drug development and treatment of many diseases, primarily of bacterial and viral nature, as well as cancers [1-4]. For instance, DNA Polymerases and Reverse Transcriptases serve as molecular targets for antiviral and antitumor chemotherapy.

With these considerations in mind, Life Chemicals has designed two polymerase-focused Libraries for drug discovery projects with a ligand-based approach:

Polymerase Focused Library – Similarity to ChEMBL Database

Over 1,200 drug-like screening compounds selected using a 2D fingerprint similarity search (Tanimoto index > 85 %) against a reference set of 20,000 compounds from the ChEMBL database with reported activity against polymerase targets:

  • DNA polymerase beta
  • DNA polymerase iota
  • DNA polymerase eta
  • Poly [ADP-ribose]polymerase-1

Polymerase Focused Library – 15 polymerase assays

Over 17,034 structurally-diverse molecules with potential polymerase inhibition activity.

First, a reference set of 4,567 biologically active compounds from 15 polymerase assays was prepared, using the data available from patents and literature publications, representing the following polymerases:

  • RNA polymerase beta subunit (EC 2.7.7.6)
  • Ribonuclease HI (RNase HI) (Ribonuclease H) (RNase H)
  • DNA Polymerase III Holoenzyme
  • Measles Virus RNA-Dependent RNA Polymerase
  • Reverse Transcriptases (HIV-1, HIV-2, West Nile Virus NS2bNS3)

The Life Chemicals HTS Compound Collection has been searched for small-molecule analogs of polymerase inhibitors in a reference set, using the MDL public keys and the Tanimoto similarity cut-off 90 %. The resulting compounds were arranged according to their similarity vs. the reference set and predicted polymerase activity, putting the most active compounds at the top of the list.

References:

  1. Garro HA, Pungitore CR. Coumarins as Potential Inhibitors of DNA Polymerases and Reverse Transcriptases. Searching New Antiretroviral and Antitumoral Drugs. Curr Drug Discov Technol. 2015;12(2):66-79. doi: 10.2174/1570163812666150716111719.
  2. Velkov T, Carbone V, Akter J, Sivanesan S, Li J, Beddoe T, Marsh GA. The RNA-dependent-RNA polymerase, an emerging antiviral drug target for the Hendra virus. Curr Drug Targets. 2014 Jan;15(1):103-13. doi: 10.2174/1389450114888131204163210. PMID: 24102407.
  3. Jiang Y, Yin W, Xu HE. RNA-dependent RNA polymerase: Structure, mechanism, and drug discovery for COVID-19. Biochem Biophys Res Commun. 2020 Sep 4:S0006-291X(20)31721-6. doi: 10.1016/j.bbrc.2020.08.116. Epub ahead of print. PMID: 32943188; PMCID: PMC7473028.
  4. Wang J, Li H, He G, Chu Z, Peng K, Ge Y, Zhu Q, Xu Y. Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy. J Med Chem. 2020 Jan 9;63(1):122-139. doi: 10.1021/acs.jmedchem.9b00622. Epub 2019 Dec 27. PMID: 31846325.
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