Helicases are a class of molecular motor proteins powered by ATP. They play a critical role in unwinding duplex polynucleotides, separating them into two individual nucleic acid strands. This unwinding process is essential for various cellular functions, such as replication, transcription, and recombination [1]. Helicases are ubiquitous in all forms of life, from viruses and bacteria to mammals, and they are indispensable for the replication and repair of their respective genomes [2]. It is only evident that DNA helicases represent promising and druggable targets for drug development in infectious diseases and cancer therapy.
Based on ligand- and receptor-based cheminformatics approaches, we designed dedicated Screening Sets consisting of more than 7,000 drug-like screening compounds of potential helicase inhibitors:
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
For a pre plated set based on this Screening Library, please explore our Pre-plated Focused Libraries.
Figure 1. Helicases in DNA replication (left, art by Armin Mortazavi [16]) and helicase superfamilies.
Helicase Focused Library
To create this helicase-focused Screening Set, we first assembled a reference set of molecules known to have helicase-related activity using data from the ChEMBL, PubChem, DrugBank, and scientific literature sources [3-7]. The reference database of 2,745 biologically active compounds from nine different helicase assays was created using the data available from patents and literature publications* encompassing the following helicase targets:
- 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)
- Bloom syndrome protein (ATP-dependent DNA helicase)
- Replication protein E1 (ATP-dependent DNA helicase)
- Eukaryotic initiation factor 4A-III (ATP-dependent RNA helicase)
- ATP-dependent RNA helicase DDX3X
- Chromo domain-containing protein 1 (helicase activity)
- DnaC helicase
- Replicase polyprotein 1ab
Subsequently, the Life Chemicals HTS Compound Collection was analyzed using MDL public keys and Tanimoto similarity cut-off of 84 % to screen for small-molecule analogs of the compounds in the reference set. As a result, over 3,800 screening compounds were identified as potential helicase inhibitors.
Figure. 2. Target distribution in the Life Chemicals Helicase Focused Library.
*Document IDs in the ChEMBL DB: CHEMBL3822370, CHEMBL4014334, CHEMBL1134109, CHEMBL1201862, CHEMBL1145280, CHEMBL1148307, CHEMBL1139458, CHEMBL4049423, CHEMBL1138995
Representative screening compounds from the Helicase Focused Library by 2D Similarity:
Helicase Targeted Library
Using in silico molecular docking, our chemoinformatics team has selected over 3,200 structurally-diverse molecules with potential activity against the following helicase-related drug targets:
SARS-CoV-2 helicase (NSP13)
NSP13 helicase plays an important role in viral RNA synthesis. In addition, SARS-CoV-2 NSP13 helicase was shown to inhibit IFN production. According to recent data, NSP13 prevents the phosphorylation of STAT1 by JAK1 kinase [8]. NSP13 also interacts with IRF3, blocking antiviral immune responses [9]. This helicase is quite conservative, making it an extremely attractive target for COVID-19. The pocket at the 5' end of the RNA-binding site is known to be one of the most well-conserved pockets in the entire SARS-CoV-2 proteome [10]. This makes it a good site of inhibition for the development of anti-COVID19 drugs. It can be assumed that such drugs can fight the current pandemic and future viral threats.
Key features:
- Method: glide ligand docking (standard precision)
- X-Ray data used: RCSB PDB ID - 7NNG
- Constraints: no
- Filters used: metabolism, QPPCaco, HumanOralAbsorption, toxicity, stars (complex QikProp parameter)
- Number of compounds selected: 1,638
Figure 3. Spatial structure binding site of the complex of NSP13 with the lead docking molecule F6548-3989.
Werner syndrome helicase (WRN)
WRN is a multifunctional enzyme with helicase and exonuclease activities and it is involved in many important pathways, including DNA replication, recombination, and repair [11]. Thus, this enzyme is an important target in cancers characterized by genomic microsatellite instability. WRN also plays a certain role in regulating bone development and growth through SHOX transcriptional regulation [12]. Inhibition of the WRN helicase has been shown to reduce the viability of BRCA2-deficient cells [13], making it an attractive target for breast and ovarian cancer. According to the published data [14-15], the ATP binding site for Werner Syndrome Helicase-Nuclease (WRN) was chosen for its inhibition. You can independently sort the compounds obtained in docking by toxicity, metabolism, adsorption, and stars.
Key features:
- Method: glide ligand docking (standard precision)
- X-ray data used: RCSB PDB ID - 6YHR
- Constraints: no
- Filters used: no
- Number of compounds selected: 1,677
Figure 4. Spatial structure binding site of the complex of WRN with the lead docking molecule F2471-1909.
References:
- Tuteja N, Tuteja R. Helicases as molecular motors: An insight. Physica A. 2006;372(1):70-83. doi:10.1016/j.physa.2006.05.014
- Frick DN, Lam AM. Understanding helicases as a means of virus control. Curr Pharm Des. 2006;12(11):1315-1338. doi:10.2174/138161206776361147
- 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 Situ Minimization // Curr Comput Aided Drug Des. 2017;13(2):160-169.
- Simon NE, Schwacha A. The Mcm2-7 replicative helicase: a promising chemotherapeutic target // Biomed Res Int. 2014;2014:549719.
- Datta A, Brosh RM Jr. New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy // Front Mol Biosci. 2018;5:59.
- 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.
- Sommers JA, Kulikowicz T, Croteau DL, et al. A high-throughput screen to identify novel small molecule inhibitors of the Werner Syndrome Helicase-Nuclease (WRN). PLoS One. 2019;14(1):e0210525. Published 2019 Jan 9. doi:10.1371/journal.pone.0210525
- Fung SY, Siu KL, Lin H, Chan CP, Yeung ML, Jin DY. SARS-CoV-2 NSP13 helicase suppresses interferon signaling by perturbing JAK1 phosphorylation of STAT1. Cell Biosci. 2022;12(1):36. Published 2022 Mar 22. doi:10.1186/s13578-022-00770-1
- Feng K, Zhang HJ, Min YQ, et al. SARS-CoV-2 NSP13 interacts with host IRF3, blocking antiviral immune responses. J Med Virol. 2023;95(6):e28881. doi:10.1002/jmv.28881
- Newman JA, Douangamath A, Yadzani S, et al. Structure, mechanism, and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase. Nat Commun. 2021;12(1):4848. Published 2021 Aug 11. doi:10.1038/s41467-021-25166-6
- Morales-Juarez DA, Jackson SP. Clinical prospects of WRN inhibition as a treatment for MSI tumors. NPJ Precis Oncol. 2022;6(1):85. Published 2022 Nov 15. doi:10.1038/s41698-022-00319-y
- Tian Y, Wang W, Lautrup S, et al. WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome. Nat Commun. 2022;13(1):5456. Published 2022 Sep 16. doi:10.1038/s41467-022-33012-6
- Datta A, Biswas K, Sommers JA, et al. WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells. Nat Commun. 2021;12(1):6561. Published 2021 Nov 12. doi:10.1038/s41467-021-26811-w
- Parker MJ, Lee H, Yao S, et al. Identification of 2-Sulfonyl/Sulfonamide Pyrimidines as Covalent Inhibitors of WRN Using a Multiplexed High-Throughput Screening Assay. Biochemistry. 2023;62(14):2147-2160. doi:10.1021/acs.biochem.2c00599
- Newman JA, Gavard AE, Lieb S, et al. Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers. Life Sci Alliance. 2020;4(1):e202000795. Published 2020 Nov 16. doi:10.26508/lsa.202000795
- https://www.scq.ubc.ca/dna-replication-not-your-office-photocopier/