Exhaustive <i>in silico</i> design and screening of novel antipsychotic compounds with improved pharmacodynamics and blood-brain barrier permeation properties

Antipsychotic drugs or neuroleptics are widely used in the treatment of psychosis as a manifestation of schizophrenia and bipolar disorder. However, their effectiveness largely depends on the blood-brain barrier (BBB) permeation (pharmacokinetics) and drug-receptor pharmacodynamics. Therefore, in this study, we developed and implemented the in silico pipeline to design novel compounds (n = 260) as leads using the standard drug scaffolds with improved PK/PD properties from the standard scaffolds. As a result, the best candidates (n = 3) were evaluated in molecular docking to interact with serotonin and dopamine receptors. Finally, haloperidol (HAL) derivative (1‐(4‐fluorophenyl)‐4‐(4‐hydroxy‐4‐{4‐[(2‐phenyl‐1,3‐thiazol‐4‐yl)methyl]phenyl}piperidin‐1‐yl)butan‐1‐one) was identified as a “magic shotgun” lead compound with better affinity to the 5-HT2A, 5-HT1D, D2, D3, and 5-HT1B receptors than the control molecule. Additionally, this hit substance was predicted to possess similar BBB permeation properties and much lower toxicological profiles in comparison to HAL. Overall, the proposed rational drug design platform for novel antipsychotic drugs based on the BBB permeation and receptor binding might be an invaluable asset for a medicinal chemist or translational pharmacologist. Communicated by Ramaswamy H. Sarma抗精神病药物（Antipsychotic drugs）与神经阻滞剂（neuroleptics）被广泛应用于以精神分裂症和双相情感障碍为表现形式的精神病治疗。然而，其临床疗效很大程度上取决于血脑屏障（blood-brain barrier, BBB）渗透能力（药代动力学特性）与药物-受体药效动力学行为。因此，本研究开发并搭建了计算机模拟研发管线（in silico pipeline），以标准药物母核为基础设计260个全新化合物作为候选分子，使其相较于原始母核具备更优异的药代动力学/药效动力学（PK/PD）特性。最终，选取3个最优候选化合物开展分子对接（molecular docking）实验，以验证其与血清素受体及多巴胺受体的结合活性。结果显示，氟哌啶醇（haloperidol, HAL）衍生物——1-(4-氟苯基)-4-(4-羟基-4-{4-[(2-苯基-1,3-噻唑-4-基)甲基]苯基}哌啶-1-基)丁-1-酮——被鉴定为“魔术霰弹”型候选化合物，其对5-HT2A、5-HT1D、D2、D3及5-HT1B受体的亲和力均优于对照药物。此外，相较于HAL，该命中化合物被预测拥有相近的血脑屏障渗透能力，且毒理学特性显著更低。总体而言，本研究提出的基于血脑屏障渗透与受体结合特性的新型抗精神病药物合理设计平台，有望为药物化学家或转化药理学家提供极具价值的研究工具。 本文由Ramaswamy H. Sarma通讯