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.

Ascorbic acid (AsA) and the nonsteroidal anti-inflammatory drug ibuprofen (IBU), adsorbed noncovalently on buckminsterfullerene C60 for its transdermal delivery, are investigated using Classical Molecular Dynamics and Density Functional Theory. Classical annealing is performed to explore the molecular configurations of both AsA and IBU adsorbed on C60, searching for optimal geometries. In particular, it is shown that IBU assumes two distinct adsorption geometries, giving rise to a two-level adsorption, leading to an extended anti-inflammatory delivery time. A vibrational analysis was also carried out for adsorbed IBU, depicting the IR and Raman spectra for both geometries. Furthermore, we investigated also the binding of IBU to human serum albumin (HSA) by using a fragmentation strategy together with a dispersion corrected exchange–correlation functional. Our computer simulations are valuable for a better understanding of the binding mechanism of AsA and IBU, looking for rational design and the development of novel drugs with improved potency.

Since the early days of migrainous research, serotonin receptors have been considered a major target of drugs, being among the most marketed one for its treatment. They are also involved in the mechanisms underlying many neurological dysfunctions. In this context, by taking advantage of their crystallographic structure co-crystallized with their agonist dihydroergotamine (DHE), one of the oldest and most widely used antimigraine drugs, a quantum chemistry study based on the electrostatically embedded molecular fractionation with conjugate caps scheme within the density functional theory formalism is performed to unveil this complex’s detailed binding energy. Furthermore, we predict the relevance of the DHE regions, as well as the influence of each protein segment to DHE–serotonin receptor binding. We believe that our work is a first step using in silico quantum design as a means to influence the discovery of new drugs to treat migraine and other diseases related to the serotonin agonist.