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 ΔG_Binding. 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.

在第二代（非典型）抗精神病药物中，阿立哌唑（ARP）作为 D2 受体（D2R）的部分激动剂非常重要。在阿立哌唑长效注射制剂领域的长期努力已导致其两种酯衍生物，阿立哌唑月桂醇 (ARP-L) 和阿立哌唑卡沃西 (ARP-C) 作为前药和非典型抗精神病药。但是，关于 ARP-L 和 ARP-C 的 D2R 绑定的信息是有限的。在此，本研究介绍了 ARP-L 和 ARP-C 的化学信息学评估、分子对接和分子动力学 (MD) 模拟，以深入了解它们的理化性质-活性关系以及它们与 D2R 与其母体药物的详细相互作用分子（ARP）。两种 ARP 衍生品，就像 ARP 本身一样，不是 PAIN，与 D3R 相比，与 D2R/D4R 的相互作用更强。这些抗精神病药与D2R的结合自由能顺序如下：ARP>ARP-C≅ARP-L。RMSD、RMSF、Rg 和 SASA 的分析表明，由于抗精神病药配体结合，细胞内区域的稳定性/波动性、柔韧性/刚性、致密性和溶剂可及表面积发生变化，而细胞内残基 (ICL1: 29-32 , ICL2: 103-114, ICL3: 188-348) 对 ΔG 没有贡献_绑定。这种看法表明存在变构通信，将正构结合口袋中的微小变化转化为细胞内区域的明显重排。大多数这种正构-变构双重效应在 D2R/ARP-C 复合物中观察到。这项工作可能有助于指导未来的药物发现和开发研究，以更好地耐受基于阿立哌唑的抗精神病药物。