Virtual screen
Mutagenic studies to support a virtual screen using HIDDEN GEM
Please go to Researchers involved for a list of researchers who contributed to this work
This project commence by a conservation analysis of the DENV Ns5 protein (RdRp) using the ENDscript2/Blast to identify conserved amino acids across the protein. Next a global and local hotspot mapping was performed by combining Fragalysis and FTMap. The combined results were analyzed looking for conserved sites, located in druggable pockets identifying four pockets of interest (labelled purple, orange, blue, and green). The four pockets were studied with saturation mutagenesis which confirmed that the Green site is a suitable pocket to target; the Green site, located close to the nucleic acid cavity of the protein, between aa 391 and 400.
Having identified the new druggable pocket called the Green site that was used to perform a virtual screen using the tool HIDDEN GEM, more information about the development of HIDDEN GEM can be found in this 2023 paper.
With HIDDEN GEM, an AI-driven virtual screen of the full Enamine REAL space was possible that generated both de novo hits (that would require synthesis) and compounds from the Enamine purchasable library. A diverse selection of 1000 compounds from the purchasable library was identified, and after further clustering and selection focusing on drug-like compounds, 100 compounds were nominated for purchase. Only 65 compounds were available and purchased for testing.
The process from start to a list of purchasable compounds took ~6 weeks.
