Schizophrenia is a neuropsychiatric disorder characterised by positive symptoms, negative symptoms, and cognitive impairment. Dopamine system dysfunction is strongly implicated in the aetiology of schizophrenia, where the hyperactivity in striatal dopamine and hypoactivity in cortical dopamine is considered the key feature of this serious mental disorder. Recent research has been directed toward finding new therapeutic agents to potentiate the D₁-receptor signalling and inhibit the D₂-receptor signalling. Two enzymes in the phosphodiesterase (PDE) family, PDE1B and PDE10A, have become desirable drug targets for psychiatric disorders in general and schizophrenia in particular due to their high expression in brain regions involved in schizophrenia. The PDE1B enzyme represents the major inactivation mechanism of D₁-receptors; therefore, the inhibition of PDE1B activity will potentiate the D₁-receptor signalling and mitigate the negative symptoms and cognitive impairments. Whereas the inhibition of PDE10A activity has generated much excitement as a potentially novel mechanism to treat the positive symptoms of schizophrenia, which are attributed to the increased dopamine D₂-receptor signalling. In which the inhibition of PDE10A activity will block the D₂-receptor signalling and improve the positive symptoms. Therefore, in the quest of searching for a new treatment for schizophrenia, we report here the identification of a novel inhibitor with dual action on PDE1B and PDE10A. A sequential pharmacophore-based virtual screening, molecular docking and molecular dynamic simulations; were combined to identify the new inhibitor. After a detailed analysis of the results, two ligands were selected for the biological evaluation, in which one of the two ligands showed significant inhibitory activity against both PDE1B and PDE10A. The newly identified inhibitor can be explored for further optimisation and evaluated in vivo for its antipsychotic-like effects.

精神分裂症是一种以阳性症状、阴性症状和认知障碍为特征的神经精神障碍。多巴胺系统功能障碍与精神分裂症的病因密切相关，其中纹状体多巴胺的过度活跃和皮质多巴胺的低活跃被认为是这种严重精神障碍的关键特征。最近的研究旨在寻找新的治疗剂来增强 D ₁受体信号传导并抑制 D ₂-受体信号。磷酸二酯酶 (PDE) 家族中的两种酶 PDE1B 和 PDE10A 已成为一般精神疾病特别是精神分裂症的理想药物靶点，因为它们在涉及精神分裂症的大脑区域中高表达。PDE1B 酶代表 D ₁受体的主要失活机制；因此，PDE1B 活性的抑制将增强 D ₁受体信号传导并减轻阴性症状和认知障碍。而 PDE10A 活性的抑制作为治疗精神分裂症阳性症状的潜在新机制引起了很多兴奋，这归因于多巴胺 D ₂的增加-受体信号。其中PDE10A活性的抑制将阻断D _{2 -}受体信号传导并改善阳性症状。因此，为了寻求精神分裂症的新疗法，我们在此报告鉴定了一种对 PDE1B 和 PDE10A 具有双重作用的新型抑制剂。基于序列药效团的虚拟筛选、分子对接和分子动力学模拟；结合以鉴定新的抑制剂。在对结果进行详细分析后，选择了两种配体进行生物学评价，其中两种配体之一对 PDE1B 和 PDE10A 均显示出显着的抑制活性。可以探索新发现的抑制剂以进一步优化并在体内评估其抗精神病药样作用。