Disorders in the central nervous system have been ascribed to impairments in the function of the AMPA ionotropic glutamate receptors (iGluRs), which are ligand-gated ion channels that undergo structural changes after activation, mediating fast synaptic transmission in the central nervous system. Experimental, computational, and crystallographic analyses have been used to describe partial agonism in AMPA receptors – mainly those related to the willardiines, namely fluorine–willardiine (FW), hydrogen–willardiine (HW), bromine–willardiine (BrW), and iodine–willardiine (IW). By employing quantum chemistry methods based on the density functional theory approach, we unveil here the detailed binding energy features of willardiines co-crystallized with the iGluRs receptors. Our computational results demonstrate that the total binding energies of the AMPA–Willardiines complex correlate with the agonist binding energies, whose experimental sequential data match our computational counterpart, excluding the HW case. Besides, it was observed that FW, BrW, and IW have significant charged states at physiological pH.