Evaluating the conformational space of the active site of D2 dopamine receptor. Scope and limitations of the standard docking methods.

M. NATALIA C. ZARYCZ; RODRIGO D. TOSSO; M. AYELÉN SCHIEL; LUISA GOICOCHEA MORO; HÉCTOR A. BALDONI; EMILIO ANGELINA ; CAMILA ADÁRVEZ-FARESÍN ; RICARDO D. ENRIZ

Rosario, Santa Fe

Congreso; L Reunión Anual de la Sociedad Argentina de Biofísica; 2022

Sociedad Argentina de Biofísica

We report here for the first time the potential energy surfaces of phenyletilamine and meta-tyramine at the D2 dopamine receptor binding site. Potential energy surfaces not only allow us to observe all the critical points of the surface (minimums, maximums, and transition states), but also to note the ease or difficulty that each local minima have for their conformational inter-conversions and therefore know the conformational flexibility that these ligands have in their active sites. Taking advantage of possessing this valuable information, we analyze how accurate a standard docking study is in these cases. Our results indicate that although we have to be careful in how to carry out this type of study and to consider performing some extra-simulations, docking calculations can be satisfactory. In order to analyze in detail the different molecular interactions that are stabilizing the different ligand-receptor complexes, we carried out quantum theory of atoms in molecules computations and NMR shielding calculations. Although some of these techniques are a bit tedious and require more computational time, our results demonstrate the importance of performing computational simulations using different types of combined techniques in order to obtain more accurate results. Our results allow us to understand in details the molecular interactions stabilizing and destabilizing the different ligand receptor complexes reported here. Thus, the different activities observed for dopamine, meta-tyramine, and phenyletilamine can be clearly explained at molecular level.