Zinc Nuclear Finger (ZNF) proteins are transcription factors possessing a finger domain. They take part in regulating various biological processes, including transcriptional control, post-transcriptional regulation, and facilitation of protein-protein interactions. A wide range of "zinc finger" domains are able to interact with DNA, RNA, PAR (poly-ADP-ribose), and other proteins. Thus, ZNFs are involved in the transcriptional regulation of ubiquitin-mediated protein degradation, signal transduction, actin targeting, DNA repair, cell migration, lipid metabolism, cell differentiation, and immune responses. This multifaceted nature of ZNF proteins offers an expansive spectrum of opportunities for drug discovery, enabling researchers to specifically target ZNF proteins and impact a multitude of critical cellular processes.
As scientific comprehension of ZNF proteins is making progress, they emerge as promising yet relatively unexplored targets for modern drug discovery. The Life Chemicals cheminformatics team has meticulously designed specialized Screening Sets comprising over 2,500 drug-like screening compounds that have the potential to target zinc nuclear finger proteins selectively:
The compound selection can be customized based on your requirements, cherry picking is available.
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Background information
ZNF proteins are distinguished by their unique DNA binding motifs, which include C2H2, LIM, RING, and PHD [1]. Among these, the most prevalent one in ZNF proteins is the C2H2 motif, typically located at the C-terminus of the proteins involved. It is characterized by a consensus sequence of CX2CX3FX5LX2HX3H and consists predominantly of hydrophobic residues, except for the C2H2 positions [2].
Among the numerous functions of ZNF proteins, one of the most abundant and extensively studied is their role as transcription factors. These proteins can recognize specific DNA sequences, enabling them to either promote or repress transcription. Additionally, ZNF proteins play a crucial role in facilitating protein-protein interactions. Some ZNF proteins, functioning as post-transcriptional regulators, possess RNA-binding properties and are primarily associated with mRNA maturation.
Significantly, ZNF proteins are intricately involved in the pathogenesis of various diseases, particularly neurodegenerative disorders such as Alzheimer's and Parkinson's, which positions them as valuable targets within the metabolic pathways relevant to these problems. For instance, they have implications in Alzheimer's disease through the inhibition of ZNF179, and in Parkinson's disease, where a pronounced effect is shown whenever ZNF746 is overexpressed [3]. Furthermore, in the case of Spinal Muscular Atrophy (SMA), the ZNF1 protein from the ZNF family acts as a protector of the SMN1 gene.
![Structure and function of classical ZFs according to [3].](img/library_descriptions/Zinc%20Nuclear%20Finger%20Protein/zinc_nuclear_finger_protein_library.jpg "Structure and function of classical ZFs according to [3].")
Figure 1. Structure and function of classical ZFs according to [3].
ZNF Protein Focused Set
To create this Screening Library, a reference set of more than 47,000 compounds with documented ZNF inhibitory activity, extracted from the ChEMBL database, was first prepared (IC50, Ki, etc., less than 10 μM, Inhibition > 50 %). Next, the Life Chemicals HTS Compound Collection was analyzed using a 2D fingerprint similarity search (Tanimoto index > 0.85) against the obtained reference set. Subsequently, the compound selection was further diversified using radial fingerprints internal dissimilarity search (Tanimoto > 0.85) to enhance the structural diversity of the screening compounds.
Finally, the resulting screening compounds were subjected to in-house MedChem filters to eliminate compounds containing PAINS (Pan-Assay Interference Compounds), toxicophores, and reactive moieties to successfully result in over 2,000 drug-like molecules, focusing on the following targets:
- Zinc finger protein GLI1
- Bromodomain adjacent to zinc finger domain protein 2B
- Zinc finger protein GLI2
- PHD finger protein 23
- Cereblon/Aiolos
- Zn finger protein
- Zinc finger CCCH-type antiviral protein 1
- Zinc finger and BTB domain-containing protein 16
- Cereblon/Zinc finger protein 692
- Zinc finger MYND domain-containing protein 11
- Zinc finger protein 664
- Zinc finger and BTB domain-containing protein 7A
- CXXC-type zinc finger protein 1
- PR domain zinc finger protein 12
- PR domain zinc finger protein 13
- CXXC-type zinc finger protein 4
- CXXC-type zinc finger protein 5
- PR domain zinc finger protein 2
- Zinc finger protein Aiolos
- PR domain zinc finger protein 1
- Cereblon/Sal-like protein 4
- Cereblon/Zinc finger protein 827
- PR domain zinc finger protein 8
- Zinc finger CW-type PWWP domain protein 1
- PR domain zinc finger protein 14
- PR domain zinc finger protein 10
- Bromodomain adjacent to zinc finger domain protein 2A
- Bromodomain and PHD finger-containing protein 3
ZNF Protein Targeted Set
RNF31, also known as HOIP, is a critical component of the linear ubiquitin chain assembly complex (LUBAC). As an E3 ubiquitin-protein ligase, RNF31 is pivotal in conjugating linear ('Met-1'-linked) polyubiquitin chains to substrates. This enzymatic activity is crucial for various cellular signaling pathways, particularly in mediating NF-kappa-B activation, which is essential for regulating immune and inflammatory responses. Structurally, the protein contains several RING finger motifs, which are present in various functionally distinct proteins and are believed to be involved in DNA interactions [5].
Based on the molecular docking results, a carefully curated set of 512 potential RING-interacting ligands was selected using compounds from the Life Chemicals HTS Compound Collection. The compound selection process was carried out with utmost care, focusing on ligands with high efficacy and binding interactions.
Key features:
- Method: high-throughput virtual screening (docking), molecular fitting
- X-Ray data used: 4LJP
- Filters used: no
- Number of compounds selected: 512
Figure 2. Best hit in the RNF31 binding site.
Representative screening compounds from the Zinc Nuclear Finger (ZNF) Protein Screening Library
Reference:
- Gray, Kristian A et al. “Genenames.org: the HGNC resources in 2015.” Nucleic acids research vol. 43, Database issue (2015): D1079-85. doi:10.1093/nar/gku1071
- Zhang, Wei, et al. “Crystal structure of the Cys2His2-type zinc finger domain of human DPF2.” Biochemical and biophysical research communications vol. 413,1 (2011): 58-61. doi:10.1016/j.bbrc.2011.08.043.
- Padjasek M, Kocyła A, Kluska K, Kerber O, Tran JB, Krężel A. Structural zinc-binding sites shaped for greater works: Structure-function relations in classical zinc finger, hook and clasp domains. J Inorg Biochem. 2020 Mar;204:110955. doi: 10.1016/j.jinorgbio.2019.110955.
- Bu, Siyuan, et al. “Zinc Finger Proteins in Neuro-Related Diseases Progression.” Frontiers in neuroscience vol. 15 760567. 18 Nov. 2021, doi:10.3389/fnins.2021.760567
- Hoshino, K., Nakazawa, S., Yokobori, T. et al. RNF31 promotes proliferation and invasion of hepatocellular carcinoma via nuclear factor kappaB activation. Sci Rep 14, 346 (2024). https://doi.org/10.1038/s41598-023-50594-3