RNA Screening Libraries | Targeted and Focused Screening Libraries | Screening Libraries

The majority of clinically-approved small-molecule drugs are established to target proteins. Meanwhile, it was shown that RNA is involved in the progression of various diseases, including infectious (virus infections, such as HIV, AIDS, hepatitis C) and metabolic ones (e.g., diabetes, cancer), as well as triplet repeat disorders (myotonic dystrophy, Huntington’s disease, etc.). Targeting RNAs with small-molecule drugs has offered new opportunities to therapeutically modulate numerous cellular processes directly regulated by them (such as transcription, splicing, translation, and epigenetic modifications), including those linked to 'undruggable' protein targets [1].

Against this background, Life Chemicals has developed exclusive RNA Screening Libraries comprising more than 29,600 drug-like small-molecule compounds with predicted RNA-binding activity.

Screening Sets by Cheminformatics Selection Methods

The following RNA-focused Screening Sets do make an excellent starting point for post-transcriptional gene regulation, antibacterial, and antiviral drug discovery research:

Please note that separate SD files for each Screening Set are available within the folder named "RNA Screening Subsets - Individual Files." In addition, the main SD file contains comprehensive information about all compounds, including the subsets they belong to, as indicated in the "Subset" column.

Diversity Sets

Three non-overlapping complementary Diversity Screening Sets of 5,120, 3,200 and 1,600 structurally-diverse molecules were prepared to provide the most-promising RNA-targeting screening compounds in a convenient manner. They are available both as solids or pre-plated assay-ready DMSO solutions. Combining these subsets allows for the formation of a more extensive diversity set of 9,920 screening compounds.

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 the assay-ready solutions based on this Screening Library, please, explore our Pre-plated RNA Diversity Screening Set and Pre-plated RNA Focused Sets.

You can also be interested in our related products:

Inhibition of RNA-binding proteins with small molecules

Figure 1. Inhibition of RNA-binding proteins with small molecules

Background

The primary function of RNA is to create proteins via translation. As known, there are three main types of RNA involved in protein synthesis (Fig. 2):

messenger RNA (mRNA): being transcribed from DNA contains the genetic blueprint to make proteins;
transfer RNA (tRNA): delivers amino acids to the ribosome and translates mRNA into proteins;
ribosomal RNA (rRNA): forms ribosomes, which are essential in protein synthesis, and links amino acids together to form coded proteins.

A non-coding RNA (ncRNA) is an RNA molecule that is not translated into a protein. Some RNAs also function as catalytic RNA (also termed ribozymes) to drive biochemical reactions (such as, protein synthesis, RNA splicing, and RNA cleavage); they can pair with auxiliary proteins to fulfill their catalytic functions. Other RNA roles include RNA editing, gene regulation, and RNA interference. These processes are carried out by a group of small regulatory RNAs, which include small nuclear RNA, microRNA, and small interfering RNA (Fig. 2) [7].

RNA also serves as the primary genetic material for viruses. While RNA mostly exists in the single-stranded form, certain RNA viruses are double-stranded.

Recently, the number of established RNA-based molecular targets has grown, with a detailed elucidation of their structural and functional relationship reported. Several small-molecule inhibitors have been successfully developed for a variety of RNA molecules [1-3]. It was shown that oncogenic microRNAs are tightly involved in the development and progression of various cancers [3]. Additionally, novel RNA-based drug discovery strategies are being considered for the treatment of pan-drug-resistant bacteria [4-6].

Classification of different types of RNAs.

Figure 2. Classification of different types of RNAs.

RNA Screening Subset by 2D Similarity Search

Initially, approximately 4000 reported molecules capable of binding to RNA have been picked out using various sources, such as SMMRNA, PDB, RBIND, FDA, NALDB, PubChem, and ChEMBL databases [1]. This initial reference set was then narrowed down (about 3200) by eliminating compounds with a low dissociation constant (K_d > 10 μM) or inhibition values (IC₅₀, etc.) below or equal to 10 μM.

Next, a 2D similarity search was conducted against the Life Chemicals HTS Compound Collection, focusing on high diversity by setting Tanimoto and Tversky indices at ≥ 0.80 and ≥ 0.85, respectively. Fragment-Based/Chemical Hashed Fingerprints were utilized to compare the structures of the compounds. To further refine the compound selection, various measures were implemented. These included, in particular, removing compounds identified as PAINS, deleting those containing reactive groups, and applying in-house developed medchem filters. As a result, over 40,000 analogs of reported RNA-inhibitors were obtained.

Then, the Library was further refined by considering chemical diversity. The main biochemical properties and physicochemical descriptors are included as supplementary data in the file. Finally, this rigorous selection process yielded over 22,300 drug-like screening compounds to be included in our RNA-focused Screening Library.

Examples of compounds from the ChEMBL database targeting different types of RNA and the processes in which these types are involved.

Figure 3. Examples of compounds from the ChEMBL database targeting different types of RNA and the processes in which these types are involved.

RNA Screening Subset by Bayesian Modeling

To prepare this RNA-focused Screening Library, the same training set of known RNA-binding compounds utilized in the RNA Focused Library by 2D Similarity Search has been used to build a Bayesian model. This approach was aimed at distinguishing "good" molecules from compounds with confirmed activity, using Bayesian categorization methodology. The construction of the Bayesian model involved both molecular fingerprints (circular FCFP6 fingerprints) and molecular properties (such as molecular weight, number of hydrogen bond acceptors, number of hydrogen bond donors, logarithm of the partition coefficient, polar surface area, number of rotatable bonds, and number of rings).

Next, the developed Bayesian model was applied to the Life Chemicals HTS Compound Collection to select screening compounds that target RNA. Molecules containing PAINS (Pan Assay Interference Compounds) and those with "bad" and reactive groups were filtered out from the resulting compound set. Overall, more than 1,000 drug-like screening compounds were selected.

RNA Screening Subset by Exact Match

We have developed this RNA Screening Subset that specifically focuses on screening compounds exhibiting 100 % similarity to known RNA inhibitors.

Our cheminformatics team carefully curated the Subset by initially gathering data on compounds with experimental RNA-inhibiting activity confirmed by various reliable sources, such as ChEMBL, PubChem, NALDB, SMMRNA, FDA databases, and extensive literature mining. Subsequently, we refined the screening set by excluding compounds with experimental activity of a dissociation constant (K_d) greater than 10 μM or inhibition values (IC₅₀, etc.) exceeding 10 μM. Additionally, a 2D duplicate search against the Life Chemicals HTS Compound Collection was performed, resulting in a final selection of 900 screening compounds with validated RNA-inhibiting activity.

Human RNA Screening Subset

Nowadays, targeting human RNA is an urgent task for finding new drugs against cancer and neurological diseases [8-9]. This area has only recently appeared in modern drug design, so the search for appropriate drug-like compounds is gaining popularity. The development of a screening library for human RNA is an important step toward identifying small molecules that selectively bind to human RNA and have the potential to be involved in new therapies for various diseases. Such libraries can aid in the identification of novel drug candidates, validate RNA targets, and identify potential new targets for drug development, making them an essential tool in modern drug design.

In this framework the Life Chemicals team has developed a novel RNA Screening Humans Subset. First, reference compounds were searched for in ChEMBL, PubChem, PDB, RBIND, FDA, NALDB, and SMMRNA and, subsequently, filtered by binding affinity to eliminate those with low binding affinity (K_d ≤ 10 μM; Inhibition, IC₅₀, etc. ≤ 10μM). The compounds were selected, using a 2D Similarity Search from the Company’s HTS Compound Collection with a Tanimoto score ≥ 0.8. Next, QikProp properties and descriptors (stars, amide, rtvFG, FISA, PISA, QPlogKp etc) were calculated for the selected compounds. Finally, the selection was refined by PAINS and Brenk filters. As a result to provide over 5,500 drug-like screening compounds that target human RNA molecules.

This Human-focused subset does not overlap with the RNA Screening Library by 2D Similarity Search to provide wider compound selection for HTS drug discovery projects.

Representative compounds from the Life Chemicals RNA-focused Screening Sets

References

Warner, K. D.; Hajdin, C. E.; Weeks, K. M. Principles for Targeting RNA with Drug-like Small Molecules. Nature Reviews Drug Discovery 2018, 17 (8), 547–558. https://doi.org/10.1038/nrd.2018.93.
Mehta A, Sonam S, Gouri I, Loharch S, Sharma DK, Parkesh R. SMMRNA: a database of small molecule modulators of RNA. Nucleic Acids Res. 2,014, 42 (Database issue): D132-41. https://doi.org/10.1093/nar/gkt976.
Di Giorgio, A.; Duca, M. Synthetic Small-Molecule RNA Ligands: Future Prospects as Therapeutic Agents. MedChemComm. Royal Society of Chemistry August 14, 2019, pp 1242–1255. https://doi.org/10.1039/c9md00195f.
Moellering RC. Linezolid: the first oxazolidinone antimicrobial. Ann. Intern. Med. 2003;138:135–142.https://doi.org/10.7326/0003-4819-138-2-200301210-00015.
Parmeciano Di Noto, G.; Molina, M. C.; Quiroga, C. Insights Into Non-Coding RNAs as Novel Antimicrobial Drugs. Frontiers in Genetics 2019, 10 (FEB). https://doi.org/10.3389/fgene.2019.00057.
Wu, P. Inhibition of RNA-binding proteins with small molecules. Nat Rev Chem 4, 441–458 (2020). https://doi.org/10.1038/s41570-020-0201-4
Wang D, Farhana A. Biochemistry, RNA Structure. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558999/
Lei B, Tian Z, Fan W, Ni B. Circular RNA: a novel biomarker and therapeutic target for human cancers. Int J Med Sci. 2019;16(2):292-301. Published 2019 Jan 1. doi:10.7150/ijms.28047
Angelbello AJ, Chen JL, Disney MD. Small molecule targeting of RNA structures in neurological disorders. Ann N Y Acad Sci. 2020;1471(1):57-71. doi:10.1111/nyas.14051