Fumbling through cryptic sites: a nsP2 Chikungunya Drug discovery case study

Chikungunya virus (CHIKV) causes Chikungunya fever (CHIKF) which is characterized by intensepolyarthralgia that can last for years Unfortunately, there is any specific treatments for CHIKF and nonstructural proteins (nsP) of CHIKV are considered potential targets2 mainly nsP2, due to its protease activity which is essential for virus replication. Many researchers had questioned the employment of apo protein in drug discovery studies because their conformations were not optimized for new ligands interactions. Aiming to ensemble the apo CHIKV nsP2 (PDB ID: 3TRK), mainly its druggable hotspots, we employed four distinct servers (FTMap, AlloSite, Metapocket and Fpocket) and Molecular Dynamics simulation (MD). The major druggable sites correlates with nsP2 active site and our MD data achieved the global minimum after 40ns. New hotspots opposed to catalytic site were revealed: K1239, D1204. Thus, we conclude that our results could aid the search of new anti-CHIKV compounds that could be allosteric inhibitors.