Characterizing aripiprazole and its ester derivatives, lauroxil and cavoxil, in interaction with dopamine D2 receptor: Molecular docking and dynamics simulations with physicochemical appraisals

Abstract

Among second-generation (atypical) antipsychotic medications, aripiprazole (ARP) is of major importance as the partial agonist of the D2 receptor (D2R). Long-standing efforts in the field of a long-acting injectable formulation of aripiprazole have led to its two ester derivatives, aripiprazole lauroxil (ARP-L) and aripiprazole cavoxil (ARP-C), as prodrugs and also as atypical antipsychotics. However, information regarding the D2R binding of ARP-L and ARP-C is limited. Herein, chemoinformatics appraisal, molecular docking, and molecular dynamics (MD) simulations of ARP-L and ARP-C are presented in this study to gain insights into their physicochemical properties-activity relationship and their detailed interaction with D2R in comparison with its parent drug molecule (ARP). Both ARP derivatives, exactly like ARP itself, are not PAIN and have stronger interactions with D2R/D4R in comparison with D3R. The order of binding free energy of these antipsychotics with D2R is as follows: ARP > ARP-C ≅ ARP-L. The analysis of RMSD, RMSF, Rg, and SASA indicate that due to antipsychotic ligand binding, the stability/fluctuation, flexibility/rigidity, compactness, and solvent accessible surface area change in the intracellular regions, while intracellular residues (ICL1: 29–32, ICL2: 103–114, ICL3: 188–348) have no contribution in ΔGBinding. This perception points to the existence of allosteric communications that transforms the small changes in the orthosteric binding pocket into noticeable rearrangements in intracellular regions. Most of this orthosteric–allosteric dual effect is observed in the D2R/ARP-C complex. This work could be useful in guiding future drug discovery and development studies aimed at better-tolerated aripiprazole-based antipsychotics.