The Story So Far
This project has reached step 4 in the AViDD hit confirmation cascade.
For this series we used the Small Molecule Antiviral Compound Collection (SMACC) library which is mined from the ChEMBL database. The SMACC library is a focused library that contains about 32,500 entries from the 2.4 million ChEMBL database, and the compounds have been specifically selected because they interact with viral targets. The SMACC library, and the conditions used to establish it, is described in a recent publication by Martin et al.
From the SMACC library, compounds active against Flaviviruses were selected, generating a focused library of approximately 2,000 compounds. This curated library was further diluted by the following criteria:
- Selectivity for DENV over other Flaviviruses
- Proper assay annotation in the original data
- The STOPLIGHT calculator
- Chemical clustering (selecting only one representative compound from each cluster)
- Additional manual inspection
- Commercial availability and cost
This generated a list of 73 compounds that were purchased and tested.
The selected compounds were screened in DENV2 and DENV4 [phenotypic assays] resulting in 10 compounds that displayed activity at 1 µL, and 50 compounds that showed activity at 10 µL. Further the library of 73 compounds was screened in a DENV2 Rdrp [picogreen assay] to determine %-inhibition. The 30 most promising compounds from these screens were selected and the IC50 was determined in the DENV Rdrp picogreen assay.
These 12 compounds showed the most promising DENV Rdrp IC50 and were evaluated further:
