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ERK inhibitors are continuously explored by the researchers due to their clinical significance in resistant tumor cell lines. Though many ERK1/2 inhibitors are reported, there is still need to identify novel hits to increase the number of molecules in clinical trials. Therefore, an urgent need is to examine the existing chemical space for ERK inhibitory potential with an aim to develop novel scaffolds which can act as potent ERKs inhibitors. In this study, Ulixertinib, a known ERK2 inhibitor was selected to perform scaffold hopping to discover new scaffolds with similar binding mode followed by molecular docking analysis of the hits with highest similarity score to determine, both the binding mode and affinity in the catalytic domain of ERK2. The top hit was then subjected to FBDD to identify side chains which could enhance the binding affinity in the catalytic domain of ERK2. Again, docking analysis was performed to validate and determine their binding affinity. Further the top hit identified after docking analysis was subjected to molecular dynamic simulations. Overall, 3 hits (ligand  6, 8  and  10 ) were found to possess optimum pharmacodynamic and pharmacokinetic profile,  in-silico , to be claimed as putative ERK2 inhibitors. This study disclosed new lead molecules with putative ERK2 inhibitory potential which may be further validated  via  biological evaluation.

Identifying novel putative ERK1/2 inhibitors via hybrid scaffold hopping –FBDD approach