Structural Dynamics of the Dopamine D2 Receptor with a Non-Basic Ligand

Progress in understanding protein-ligand interactions is revolutionizing drug design, especially for G protein-coupled receptors (GPCRs), which are targets for 35% of marketed drugs. The dopamine D2 receptor (D2R) represents a key drug target in schizophrenia and Parkinson's disease. While structural studies have clarified its interactions with classical ligands, the behavior of atypical, non-basic ligands like D2AAK2 remains unclear. Notably, D2AAK2 shows strong selectivity for D2R over the closely related D3R, despite identical binding pocket composition. Here, we present a cryo-EM structure of D2AAK2 bound to D2R, showing that aspartate 3.32 serves as the main anchoring point, even though the compound lacks a basic nitrogen atom. Using enhanced sampling molecular dynamics simulations and experimental approaches, we uncover a complex binding energy landscape. Simulations suggest that D2AAK2 receptor subtype selectivity between identical binding sites arises from different energy barriers for their conformational changes. Non-basic ligands offer advantages such as better brain penetration and improved pharmacokinetics. This study provides the first structural insights into a non-basic ligand targeting D2R, paving the way for developing more effective, selective drugs.