Polymerases are key enzymes for the synthesis of nucleic acid polymers. It plays a crucial role in DNA metabolism, regulating different processes such as mitosis, damage repair, transcription and replication. Therefore, the family of these crucial proteins can be valuable targets for drug development and treatment of many diseases, mainly of bacterial and viral in nature, as well as cancers. For example, DNA polymerases and reverse transcriptases can be used as molecular targets for antiviral and antitumor chemotherapy.
DNA and RNA Polymerase
DNA polymerase plays an important role in cellular replication of DNA. So far, five DNA polymerases have been found, namely DNA polymerase I, II, III, IV and V, all related to the extension of the DNA chain.
DNA polymerase and RNA polymerase are the same in that both of them can use DNA as a template for the polymerization reaction of nucleotides or deoxyribonucleotides. The differences between DNA polymerase and RNA polymerase are:
- The role of the substrate is different: The substrate of RNA polymerase is NTP, while the substrate of DNA polymerase is dNTP
- RNA polymerase does not require primers, while DNA polymerase needs primers to function
- RNA polymerase itself has certain deconvolution function, while DNA polymerase does not have this function and the deconvolution enzyme and topoisomerase are required when unwinding the double-strand
- RNA polymerase only has polymerase activity from 5'- to 3'-end, while DNA polymerase not only has polymerase activity from 5'- to 3'-end, but also has exonuclease activity from 5'- to 3'-end exonuclease activity. The fidelity of replication therefore is higher than that of transcription since the proofreading of DNA replication is ensured
- RNA polymerase usually acts in the transcription process, while DNA polymerase usually acts in the DNA replication process
BOC Sciences has abilities in designing two polymerase-focused libraries for drug discovery projects by using a ligand-based approach.
Figure 1. Screening mutant libraries of RNA polymerase. (Siegmund, V.; et al. 2012)
Library Design
Polymerase Focused Library based on the similarity to commercial databases
BOC Sciences has employed a 2D fingerprint similarity search (Tanimoto index >85%) against a reference set of 20,000 compounds in the database with reported activity against the following polymerase targets to generate over 1,200 drug-like screening compounds:
- DNA polymerase β
- DNA polymerase ion
- DNA polymerase eta
- Poly[ADP-ribose] polymerase-1
DNA Polymerase Focused Library based on polymerase assays
a. Firstly, a reference set of 4,000 bioactive compounds from 15 polymerase assays is produced using data provided in patents and literature publications, representing the following polymerases:
- RNA polymerase beta subunit
- Ribonucleases HI/H (RNase HI/H)
- DNA polymerase III holoenzyme
- Measles virus RNA-dependent RNA polymerase
- Reverse transcriptases (HIV-1, HIV-2, West Nile virus NS2bNS3)
b. The Tanimoto similarity cut-off 90% is applied against the BOC Sciences HTS compounds collection to search for small molecule analogues of polymerase inhibitors
c. Finally, the resulting compounds are ranked according to their similarity vs. the reference set and predicted polymerase activity, yielding over 17,000 structurally diverse molecules with potential polymerase inhibitory activity
DNA and RNA Polymerase Screening Library Characteristics
- No PAINS or toxic substances/unwanted functions: filtered by strict ‘Ro5-like’ physicochemical and most stringent in-house structural filters
- All PAIN and reactive compounds are excluded from selection by internal filter applications
- Confirmed bioactivity and safety via preclinical studies and clinical trials
- Structural diversity, significant efficacy, and cellular penetration
- Structural document, IC50, and other chemical and biological data are provided
- All compounds are continually updated
- Compound cherry-picking service is provided
What We Deliver
- Delivered within 2 weeks in any customer-preferred format
- Powders, dry films or DMSO solutions formatted in vials, 96 or 384-well plates
- All compounds have a minimum purity of 90% assessed by 1H NMR and HPLC
- Analytical data is provided
BOC Sciences provides professional, rapid and high-quality services of DNA and RNA Polymerase Screening Library design at competitive prices for global customers. Personalized and customized services of DNA and RNA Polymerase Screening Library design can satisfy any innovative scientific study demands. Our clients have direct access to our staff and prompt feedback to their inquiries. If you are interested in our services, please contact us immediately!
Reference
- Siegmund, V.; et al. Screening mutant libraries of T7 RNA polymerase for candidates with increased acceptance of 2′-modified nucleotides. Chemical Communications. 2012. 48(79): 9870-9872.
