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 . 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 17,000 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 188.8.131.52)
- 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.
- 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.
- 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.
- 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.
- 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.