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

ZARYCZ, M.N.C; TOSSO R.D.; SCHIEL, M.A.; GOICOCHEA MORO, L.; BALDONI, H.A.; ANGELINA, E.; ADARVEZ-FARESÍN, C.; ENRIZ, R.D.

Rosario

Congreso; L Anual Reunion of the Argentine Biophysics Society; 2022

Sociedad Argentina de Biofisica

We report here for the first time the potential energy surfaces (PES) of phenyletilamine(PEA) and meta-tyramine (m-OH-PEA) at the D2 dopamine receptor (D2DR) binding site.PESs 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 localminima have for their conformational inter-conversions and therefore know theconformational flexibility that these ligands have in their active sites. Taking advantage ofpossessing this valuable information, we analyze how accurate a standard docking studyis in these cases. Our results indicate that although we have to be careful in how to carryout this type of study and to consider performing some extra-simulations, dockingcalculations can be satisfactory. In order to analyze in detail the different molecularinteractions that are stabilizing the different ligand-receptor (L-R) complexes, we carriedout quantum theory of atoms in molecules (QTAIM) computations and NMR shieldingcalculations. Although some of these techniques are a bit tedious and require morecomputational time, our results demonstrate the importance of performing computationalsimulations using different types of combined techniques (docking/MD/hybrid QM-MM/QTAIM and NMR shielding calculations) in order to obtain more accurate results. Ourresults allow us to understand in details the molecular interactions stabilizing anddestabilizing the different L-R complexes reported here. Thus, the different activitiesobserved for dopamine (DA), m-OH-PEA, and PEA can be clearly explained at molecularlevel.