Home
Welcome to the CNP18-DENVRdrp-VirtualScreen wiki!
This repository outlines one of several projects related to our efforts to identify a small molecular compound that binds to the Dengue virus RNA-dependent RNA polymerase (RdRp). This specific repository describes our efforts at identifying a possible hit molecule from the Enamine REAL library.
Below is a summary of the project, and the sidebar to the the right allows you to explore each step if the process further; linking to additional data, tables, and other overviews we might only reference below.
To get an overview of the READDI-AViDD project please read the Rules of Participation and Origins of the Project.
You can also explore Other Repositories related to Dengue RdRp campaign.
In mid-2023 we started a virtual screening campaign of the Enamine REAL space to help us identify new starting points for developing a probe that binds to Dengue RdRp. To guide the virtual screen, mutagenic studies supported the identification of highly conserved residues on the protein, and a previously unexplored pocket on the RdRp was identified. Using HIDDEN-GEM a preliminary library of ~1000 compounds was generated and of these 65 were send for initial testing.
This generated three hits that were used as starting point for further exploration. Initially, these showed only antiviral activity but later tests using a WaveDelta assay showed they are likely binding to RdRp. Before this data arrives a first tentative exploration for the three hits was selected from commercially available sources. These should provide information about what parts are important for binding and will guide future SAR exploration.
Additional data for these hits show that RA-3301 is the top compound due to favorable aggregation profile and interaction with the DENV2 RdRp in a gelbased assay. Compound 3318 also showed moderate properties in aggregation assay and the gelbased assay, while RA-3272 does not seem to interact with the target in the gelbased assay.
In Q1 of 2024, we sent the expansion to the AViDD labs for testing and the results of these efforts are summarized here. Initial data from the whole cell assay test show that an analogue of RA-3301, compound RA-20636, shows a similar EC50 as the parent compound but improved CC50. Notably, in this compound the motif that presented as a possible PAIN in the parent compound has been removed.
April 2024
- Expansion sent for testing in SPR at SGC Toronto
- Expansion sent for testing on whole cell in Hirsch Lab
- Expansion sent for testing in gelbased assay in Gotte Lab
- Co-crystal efforts ongoing in Arnold Lab
- Testing hits on mutagenic strains in plannig to support confirmation of binding mode - Baric Lab
- Chemistry being planned to expand on the new hits