The Pivotal Distinction between Antagonists' and Agonists' Binding into Dopamine D4 Receptor-MD and FMO/PIEDA Studies.

The dopamine D4 receptor (D4R) is a promising therapeutic target in widespread diseases, and the search for novel agonists and antagonists appears to be clinically relevant. The mechanism of binding to the receptor (R) for antagonists and agonists varies. In the present study, we conducted an in-depth computational study, teasing out key similarities and differences in binding modes, complex dynamics, and binding energies for D4R agonists and antagonists. The dynamic network method was applied to investigate the communication paths between the ligand (L) and G-protein binding site (GBS) of human D4R. Finally, the fragment molecular orbitals with pair interaction energy decomposition analysis (FMO/PIEDA) scheme was used to estimate the binding energies of L-R complexes. We found that a strong salt bridge with D3.32 initiates the inhibition of the dopamine D4 receptor. This interaction also occurs in the binding of agonists, but the change in the receptor conformation to the active state starts with interaction with cysteine C3.36. Such a mechanism may arise in the case of agonists unable to form a hydrogen bond with the serine S5.46, considered, so far, to be crucial in the activation of GPCRs. The energy calculations using the FMO/PIEDA method indicate that antagonists show higher residue occupancy of the receptor binding site than agonists, suggesting they could form relatively more stable complexes. Additionally, antagonists were characterized by repulsive interactions with S5.46 distinguishing them from agonists.