Extracellular signal-regulated kinase 2 (ERK-2) is a serine/threonine protein kinase in eukaryotic cells and belongs to the mitogen-activated protein kinase (MAPK) family. An activated form of ERK-2 phosphorylates substrates in the nucleus or cytoplasm and causes specific proteins to be expressed or activated, regulating cell proliferation, differentiation and other functions. Caffeic acid (3,4 - dihydroxy cinnamic acid), as previously reported, directly interacts with ERK-2 and reduces its effects in vitro. It is also reported to have a variety of pharmacological effects, including anti-inflammatory, immunomodulatory, antioxidant and anticancer activities. In the current study, a deep-learning protocol was employed to develop effective 100 compounds by modifying the chemical structure of DHC to improve its inhibitory performance against ERK-2. Calculations of physicochemical properties for those compounds revealed that 20 compounds had drug scores better than DHC (≥ 80%). Following that, molecular docking calculations were performed on the selected compounds and DHC. The obtained data revealed that five compounds had docking scores better than DHC (≥ -5.9 kcal/mol). Moreover, data from molecular mechanics and the Poisson - Boltzmann surface area (MM/PBSA) binding energy over 200 ns MD simulation confirmed that Cmd-1 and Cmd-4 exhibited higher stability with ΔGbinding of -40.8 and -49.1 kcal/mol, respectively, which is better than DHC (-35.1 kcal/mol). Finally, various energetic and structural studies showed the high stability of the two generated compounds within the active site of ERK-2. This study highlights the potential use of Cmd-1 and Cmd-4 as promising anti-ERK-2 drug candidates.Communicated by Ramaswamy H. Sarma.