Faculty of Pharmaceutical Sciences, UCSI University, Jalan Menara Gading, Taman Connaught, 56000, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia.
Faculty of Pharmaceutical Sciences, UCSI University, Jalan Menara Gading, Taman Connaught, 56000, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia.
Comput Biol Chem. 2018 Dec;77:52-63. doi: 10.1016/j.compbiolchem.2018.09.001. Epub 2018 Sep 8.
The major complaint that most of the schizophrenic patients' face is the cognitive impairment which affects the patient's quality of life. The current antipsychotic drugs treat only the positive symptoms without alleviating the negative or cognitive symptoms of the disease. In addition, the existing therapies are known to produce extrapyramidal side effects that affect the patient adherence to the treatment. PDE10A inhibitor is the new therapeutic approach which has been proven to be effective in alleviating the negative and cognitive symptoms of the disease. A number of PDE10A inhibitors have been developed, but no inhibitor has made it beyond the clinical trials so far. Thus, the present study has been conducted to identify a PDE10A inhibitor from natural sources to be used as a lead compound for the designing of novel selective PDE10A inhibitors. Ligand and structure-based pharmacophore models for PDE10A inhibitors were generated and employed for virtual screening of universal natural products database. From the virtual screening results, 37 compounds were docked into the active site of the PDE10A. Out of 37 compounds, three inhibitors showed the highest affinity for PDE10A where UNPD216549 showed the lowest binding energy and has been chosen as starting point for designing of novel PDE10A inhibitors. The structure-activity-relationship studies assisted in designing of selective PDE10A inhibitors. The optimization of the substituents on the phenyl ring resulted in 26 derivatives with lower binding energy with PDE10A as compared to the lead compound. Among these, MA 8 and MA 98 exhibited the highest affinity for PDE10A with binding energy (-10.90 Kcal/mol).
大多数精神分裂症患者的主要抱怨是认知障碍，这影响了他们的生活质量。目前的抗精神病药物只能治疗阳性症状，而不能缓解疾病的阴性或认知症状。此外，现有的治疗方法已知会产生影响患者对治疗的依从性的锥体外系副作用。PDE10A 抑制剂是一种新的治疗方法，已被证明能有效缓解疾病的阴性和认知症状。已经开发了许多 PDE10A 抑制剂，但到目前为止，没有一种抑制剂能通过临床试验。因此，本研究旨在从天然来源中鉴定出一种 PDE10A 抑制剂，作为设计新型选择性 PDE10A 抑制剂的先导化合物。生成了针对 PDE10A 抑制剂的配体和基于结构的药效团模型，并将其用于虚拟筛选通用天然产物数据库。从虚拟筛选结果中，有 37 种化合物与 PDE10A 的活性部位结合。在这 37 种化合物中，有 3 种抑制剂对 PDE10A 表现出最高的亲和力，其中 UNPD216549 的结合能最低，被选为设计新型 PDE10A 抑制剂的起点。构效关系研究有助于设计选择性 PDE10A 抑制剂。苯环上取代基的优化导致 26 种衍生物与 PDE10A 的结合能低于先导化合物。在这些衍生物中，MA 8 和 MA 98 对 PDE10A 的亲和力最高，结合能为-10.90 Kcal/mol。
