Chikungunya virus (CHIKV) causes epidemic fever and chronic arthritis lasting months to years. No antiviral drug is approved yet. The viral nsP3 macrodomain hydrolyzes ADP-ribose and suppresses NF-κB signaling which are two essential functions for replication and immune evasion. Previous research have identified inhibitors, but no potent non-covalent inhibitor has progressed. This project will discover novel macrodomain inhibitors through trillion-scale chemical space searching. Using CHIKV nsP3 crystal structures, we will perform Chemical Space Docking. HYDE scoring will rank binding affinity, ReCore will enable scaffold hopping from weak fragment hits, FastGrow will guide expansion into adjacent subpockets and top candidates will undergo molecular dynamics simulations (100 ns) and ADMET analysis.
Nehal intends to achieve the following milestones:
- Analyze CHIKV nsP3 macrodomain pockets, map ADP-ribose binding site residues, make pharmacophore models, and perform Chemical Space Docking.
- Run HPSee docking, screen compounds based on physicochemical properties, and run MDS with MM-GBSA B.E. calculations for top compounds.
- Merge fragments using ReCore, replace the core scaffold with other groups, design analogues and run ADMET analysis.