Antiviral Screening Compound Libraries

Pursuing its research within the most pressing domains of medicinal chemistry, our cheminformatics team has created a specialized collection of non-overlapping Antiviral Libraries designed for high throughput screening (HTS) and high content screening (HCS) drug discovery projects. In total, these Screening Sets comprise over 20,000 drug-like screening compounds with potential antiviral activity:

• Antiviral Library by 2D Similarity (15,400 compounds)
• Antiviral Library by Combined Ligand-based and Structure-based Approaches (3,500 compounds)
• Antiviral Targeted Library (1,300 compounds)

Furthermore, we offer an expanded Merged Antiviral Screening Superset, encompassing more than 45,500 small-molecule compounds that include individual screening subsets for various viral diseases, all consolidated in one resource:

• Antiviral Screening Compound Libraries
• Anti-hepatitis Screening Libraries
• Anti-HIV Screening Libraries
• Coronavirus Screening Libraries
• Human Endogenous Retrovirus K (HERV-K) Inhibitor Library

For detailed information on each dedicated screening set, as well as separate SD files, please refer to the respective links provided above. The Rule of Five (Ro5) compliance is indicated for each compound.

The compound selection can be customized as per 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.

Representative compounds from the Antiviral Screening Compound Libraries

F2490-0059

F6789-0505

F1146-0147

F2094-0107

F0018-0429

F0412-0179

F0207-0033

F2333-0180

F6247-1814

F2234-0176

F3385-3041

F6795-2214

F0231-0149

F3184-0021

F2261-0014

F2173-0607

F1129-1018

F6798-5323

Background information

Addressing viral diseases through antiviral drugs and vaccines remains an ongoing challenge due to the vast array of diseases caused by viruses. Of special concern is the absence of universal treatments. The initial hurdle in antiviral drug discovery is the diversity of virus serotypes, making our efforts to tackle the problem even more complicated. Treatment failure often occurs due to drug resistance emerging from virus mutations. Additionally, most viral metabolic processes overlap with those of host cells, resulting in greater complexities in developing selective antiviral drugs. Fortunately, certain viral enzymes and multifunctional viral proteins, such as capsid proteins, do not exist in human cells, which enables us to use them as attractive targets for antiviral drug development.

In 2022, emphasizing the acute need for new antiviral medical products, the World Health Organization reported that more than 630,000 individuals worldwide died of HIV-related illnesses [1]. Chronic hepatitis C infection, as of 2019 data, contributes to around 400,000 annual deaths. Hepatitis B, also in 2019, was responsible for an estimated 820,000 deaths, primarily resulting from cirrhosis and hepatocellular carcinoma. Furthermore, in 2019, the world faced a pandemic caused by SARS-CoV-2, with the global death toll from COVID-19 surpassing 6 million [2]. These statistics bring to the forefront the development of potent antiviral drugs capable of combating the constantly changing nature of virus genomes.

Antiviral Library by 2D Similarity

This Antiviral Screening Compound Library was designed with a 2D fingerprint similarity search against the reference set of 46,518 biologically active compounds (IC₅₀, K_i, etc. less than 10 μM, Inhibition > 25%) from therapeutically relevant viral assays representing different virus species and their proteins of interest (extracted from Binding, ChEBI, PubChem and ChEMBL databases):

Then, the Life Chemicals HTS Compound Collection was filtered for analogs of molecules with known activity against different virus species and viral targets, using Tanimoto 80 % similarity cut-off on MDL public keys fingerprints. In total,over 15,400 unique structurally diverse compounds were picked out for this Screening Set.

Antiviral Library by Combined Ligand-Based and Structure-Based Approaches

The reference set of antiviral molecules was then extracted from the ChEMBLdb (v26). The compounds with the highest reported antiviral activity (IC₅₀ less than 1–1.5 uM) against each target were clustered. The top compounds from each group were docked into the corresponding target’s crystal structure to obtain bioactive conformation.

For the targets with unresolved structures, bioactive conformations of inhibitors were predicted utilizing the rigid alignment of generated conformers and statistical analysis. These aligned structures were further used for pharmacophore modeling in silico. Both Glide docking and UNITY pharmacophore search methods were employed to select the most promising antiviral-associated compounds (Fig. 2).

Combined ligand-based and structure-based approaches employed for the design of this Antiviral Library provide the method cross-validation and a higher degree of accuracy. As a result, over 3,500 potential antiviral agents were identified within the Life Chemicals HTS Compound Collection (Fig. 3). All PAINs and reactive compounds were excluded from the selection by in-house MedChem filters.

Figure 2. Example of the reference compound CHEMBL93512, an inhibitor of NS3 protease/helicase, (left) and its conformers (right). The desired pharmacophore features located on atomic centers of the native ligand are highlighted, e.g., hydrophobic centers in red. 

Figure 3. Distribution of compounds related to the selected RCSB PDB structures in the Life Chemicals Antiviral Library by Combined Ligand-Based and Structure-Based Approaches

Antiviral Targeted Library

The Life Chemicals team has developed a library of drug-like compounds based on the structure-based virtual screening, taking advantage of Phase (receptor-ligand complex) and our proprietary HTS Compound Collection. The results were filtered by similarity parameters regarding the pharmacophore hypothesis related to structure-based virtual screening (PhaseScreenScore). After that, the obtained compounds were not filtered additionally. However, based on a customer’s request, the Screening Set can be customized, for example, expanded by a specific protein target or filtered by physicochemical parameters, biological activity, metabolism, toxicity, etc.

This set contains 1,300 structurally diverse molecules identified by structural virtual screening against targets relevant in antiviral therapy:

• Hepatitis B virus core protein
• Influenza A virus PA endonuclease

Hepatitis B virus core protein

Almost 300 million people worldwide suffer from chronic hepatitis B virus (HBV) infection. About 887,000 people die each year from complications of liver cirrhosis and hepatocellular carcinoma (HCC) [8]. HCC is the sixth most common cancer among all types. One of the main factors causing HCC is HBV [9]. The core protein of HBV is involved in most stages of the viral life cycle and plays a variety of roles in HBV replication and pathogenesis [10]. To search for compounds targeting HBV core protein, we used the PDB structure of HBV core protein with a recently discovered allosteric modulator (Linvencorvir) complex, which is a promising drug for the treatment of HBV [11].

Key features:

• Method: structure-based virtual screening using Phase (receptor-ligand complex)
• X-Ray data used: 8I71
• Filters used: no
• Number of compounds selected: 715

Figure 4. Compound F3234-1503 (pink) in the binding site of hepatitis B virus core protein with allosteric modulator (green) complex (PhaseScreenScore = 2.3082).

Influenza A virus PA endonuclease

The influenza virus causes 650,000 deaths yearly [12]. The emergence of new highly pathogenic and drug-resistant influenza strains prompts the development of new therapeutic agents. The endonuclease activity of the RNA polymerase of the influenza A virus allows digestion of the host's mRNA. The PA endonuclease domain is highly conserved among different influenza virus subtypes [13]. It can also inhibit virus proliferation at the initial stage of mRNA synthesis. This makes it a promising broad-spectrum therapeutic target against influenza. We present a set of promising compounds with potential action on PA endonuclease. Our studies were based on the PA endonuclease with the inhibitor complex. The inhibitor was developed based on an HIV inhibitor (Retrovir), which demonstrated moderate activity against endonuclease. When developing this inhibitor, the authors paid particular attention to conserved residues and reducing resistance to mutations [14].

Key features:

• Method: structure-based virtual screening using Phase (receptor-ligand complex)
• X-Ray data used: 6VIV
• Filters used: no
• Number of compounds selected: 635

Figure 5. Compound F0611-0296 (pink) in the binding site of influenza A virus PA endonuclease with inhibitor (green) complex (PhaseScreenScore = 1.988)

References: 

1. World Health Organization. https://www.who.int/

2. Aleem A, Akbar Samad AB, Vaqar S. Emerging Variants of SARS-CoV-2 and Novel Therapeutics Against Coronavirus (COVID-19) [Updated 2023 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK570580/

3. De Clercq E, Li G. Approved Antiviral Drugs over the Past 50 Years // Clin Microbiol Rev. 2016 Jul;29(3):695-747. doi: 10.1128/CMR.00102-15.

4. Frange P, Leruez-Ville M. Maribavir, brincidofovir and letermovir: Efficacy and safety of new antiviral drugs for treating cytomegalovirus infections // Med Mal Infect. 2018 Dec;48(8):495-502. doi: 10.1016/j.medmal.2018.03.006.

5. Nováková L, Pavlík J, Chrenková L, Martinec O, Červený L. Current antiviral drugs and their analysis in biological materials-Part I: Antivirals against respiratory and herpes viruses // J Pharm Biomed Anal. 2018 Jan 5;147:400-416. doi: 10.1016/j.jpba.2017.06.071.

6. Mantero M, Rogliani P, Cazzola M, Blasi F, Di Pasquale M. Emerging antibacterial and antiviral drugs for treating respiratory tract infections // Expert Opin Emerg Drugs. 2018 Sep;23(3):185-199. doi: 10.1080/14728214.2018.1504020.

7. Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses - drug discovery and therapeutic options // Nat Rev Drug Discov. 2016 May;15(5):327-47. doi: 10.1038/nrd.2015.37. 

8. Liu H, Xi J, Hu J. Regulation of Hepatitis B Virus Replication by Cyclin Docking Motifs in Core Protein. J Virol. 2021 May 24;95(12):e00230-21. doi: 10.1128/JVI.00230-21. PMID: 33789995; PMCID: PMC8316097.

9. Lefeuvre C, Le Guillou-Guillemette H, Ducancelle A. A Pleiotropic Role of the Hepatitis B Virus Core Protein in Hepatocarcinogenesis. Int J Mol Sci. 2021 Dec 20;22(24):13651. doi: 10.3390/ijms222413651. PMID: 34948447; PMCID: PMC8707456.

10. Kim C, Barnes LF, Schlicksup CJ, Patterson AJ, Bothner B, Jarrold MF, Wang CJ, Zlotnick A. Core Protein-Directed Antivirals and Importin β Can Synergistically Disrupt Hepatitis B Virus Capsids. J Virol. 2022 Jan 26;96(2):e0139521. doi: 10.1128/JVI.01395-21. Epub 2021 Oct 27. PMID: 34705562; PMCID: PMC8791275.

11. Zhang W, Guo L, Liu H, et al. Discovery of Linvencorvir (RG7907), a Hepatitis B Virus Core Protein Allosteric Modulator, for the Treatment of Chronic HBV Infection. J Med Chem. 2023;66(6):4253-4270. doi:10.1021/acs.jmedchem.3c00173

12. Zhao J, Wang J, Pang X, Liu Z, Li Q, Yi D, Zhang Y, Fang X, Zhang T, Zhou R, Zhang T, Guo Z, Liu W, Li X, Liang C, Deng T, Guo F, Yu L, Cen S. An anti-influenza A virus microbial metabolite acts by degrading viral endonuclease PA. Nat Commun. 2022 Apr 19;13(1):2079. doi: 10.1038/s41467-022-29690-x. Erratum in: Nat Commun. 2023 Jun 23;14(1):3756. PMID: 35440123; PMCID: PMC9019042.

13. Meng X, Wang Y. Drug Repurposing for Influenza Virus Polymerase Acidic (PA) Endonuclease Inhibitor. Molecules. 2021 Dec 2;26(23):7326. doi: 10.3390/molecules26237326. PMID: 34885905; PMCID: PMC8659148.

14. Slavish PJ, Cuypers MG, Rimmer MA, et al. Chemical scaffold recycling: Structure-guided conversion of an HIV integrase inhibitor into a potent influenza virus RNA-dependent RNA polymerase inhibitor designed to minimize resistance potential. Eur J Med Chem. 2023;247:115035. doi:10.1016/j.ejmech.2022.115035