PDE delta is a small protein that binds and controls the trafficking of RAS subfamily proteins. Its inhibition protects initiation of RAS signaling, and it is one of the common targets considered for oncological drug development. In this study, we used solved x-ray structures of inhibitor-bound PDE delta targets to investigate mechanisms of action of six independent all-atom MD simulations. An analysis of atomic simulations combined with the molecular mechanic-Poisson-Boltzmann solvent accessible surface area/generalized Born solvent accessible surface area calculations led to the identification of action mechanisms for a panel of novel PDE delta inhibitors. To the best of our knowledge, this study is one of the first in silico investigations on co-crystallized PDE delta protein. A detailed atomic-scale understanding of the molecular mechanism of PDE delta inhibition may assist in the design of novel PDE delta inhibitors. One of the most common side effects for diverse small molecules/kinase inhibitors is their off-target interactions with cardiac ion channels and human-ether-a-go-go channel specifically. Thus, all of the studied PDE delta inhibitors are also screened in silico at the central cavities of hERG1 potassium channels.