Combating viral diseases with antiviral drugs and/or vaccines remains a persistent challenge due to a wide diversity of diseases caused by viruses and the absence of universal treatments. The variety of serotypes (or serovars) is the first complexity faced by antiviral drug discovery. Drug resistance caused by emerging virus mutations remains a major cause of treatment failure. This stimulates a vital need for potent antiviral drugs that could counteract the highly variable nature of virus genomes.
Additionally, the majority of metabolic processes of viruses are shared with those of host cells, further complicating the development of selective antiviral drugs. Fortunately, there are some specific viral enzymes and multifunctional viral proteins (such as capsid proteins) that are absent in human cells, making them attractive antiviral drug targets.
Life Chemicals has designed its dedicated Antiviral Libraries of over 13,700 drug-like screening compounds with potential antiviral activity for high throughput screening (HTS) and high content screening (HCS) projects:
- Antiviral Library by 2D Similarity (10,100 compounds)
- Antiviral Library by Combined Ligand-based and Structure-based Approaches (3,500 compounds)
It should be emphasized that these antiviral screening compound sets are not overlapping. Ro5 compliance is indicated for each compound and cherry-picking is available.
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Antiviral Library by 2D Similarity
This Antiviral Screening Compound Library was designed with 2D fingerprint similarity search against the reference set of 41,514 biologically active compounds (IC50, Ki, etc. less than 10 μM, Inhibition > 25%) from therapeutically relevant viral assays representing different virus species and their proteins of interest (extracted from Binding and ChEMBL databases):
After filtering and merging their activity type data, the resulting 19,244 unique compounds were obtained and used as a basis for the Library design.
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. Applying a combination of the organism- and single protein-type research data led to the creation of two subsets containing almost 6,000 small-molecule analogs against virus organisms and 4,200 compounds targeting viral proteins (Fig. 1).
In total, over 10,150 unique structurally diverse compounds were selected for the Life Chemicals Antiviral Library by 2D Similarity.
Figure 1. Distribution of compounds from the Antiviral Library by 2D Similarity according to different virus types (A) and their targets (B).
Antiviral Library by Combined Ligand-Based and Structure-Based Approaches
In order to identify key features of a protein-ligand binding mechanism, the relevant protein crystal structures of the most interesting and widely spread antiviral molecular targets were first collected from the RCSB Protein Data Bank. Selected target examples are shown below:
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 with 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 application.
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
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