Bukhari Syed Nasir Abbas, Elsherif Mervat Abdelaziz, Junaid Kashaf, Ejaz Hasan, Alam Pravej, Samad Abdul, Jawarkar Rahul D, Masand Vijay H
Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72388, Saudi Arabia.
Chemistry Department, College of Science, Jouf University, Sakaka 72388, Saudi Arabia.
Pharmaceuticals (Basel). 2022 Jul 5;15(7):834. doi: 10.3390/ph15070834.
The 5-hydroxytryptamine receptor 6 (5-HT6) has gained attention as a target for developing therapeutics for Alzheimer's disease, schizophrenia, cognitive dysfunctions, anxiety, and depression, to list a few. In the present analysis, a larger and diverse dataset of 1278 molecules covering a broad chemical and activity space was used to identify visual and concealed structural features associated with binding affinity for 5-HT6. For this, quantitative structure-activity relationships (QSAR) and molecular docking analyses were executed. This led to the development of a statistically robust QSAR model with a balance of excellent predictivity (R = 0.78, R = 0.77), the identification of unreported aspects of known features, and also novel mechanistic interpretations. Molecular docking and QSAR provided similar as well as complementary results. The present analysis indicates that the partial charges on ring carbons present within four bonds from a sulfur atom, the occurrence of sp3-hybridized carbon atoms bonded with donor atoms, and a conditional occurrence of lipophilic atoms/groups from nitrogen atoms, which are prominent but unreported pharmacophores that should be considered while optimizing a molecule for 5-HT6. Thus, the present analysis led to identification of some novel unreported structural features that govern the binding affinity of a molecule. The results could be beneficial in optimizing the molecules for 5-HT6.
5-羟色胺受体6（5-HT6）作为开发治疗阿尔茨海默病、精神分裂症、认知功能障碍、焦虑症和抑郁症等疾病的治疗药物的靶点，已受到关注。在本分析中，使用了一个更大且多样的包含1278个分子的数据集，该数据集涵盖了广泛的化学和活性空间，以识别与5-HT6结合亲和力相关的可见和隐藏结构特征。为此，进行了定量构效关系（QSAR）和分子对接分析。这导致开发出一个统计稳健的QSAR模型，该模型具有出色的预测性（R = 0.78，R = 0.77），识别出已知特征未报告的方面，以及新颖的机理解释。分子对接和QSAR提供了相似且互补的结果。本分析表明，与硫原子相距四个键以内的环碳上的部分电荷、与供体原子键合的sp3杂化碳原子的存在，以及来自氮原子的亲脂性原子/基团的条件性出现，这些是突出但未报告的药效基团，在优化针对5-HT6的分子时应予以考虑。因此，本分析导致识别出一些控制分子结合亲和力的新颖未报告结构特征。这些结果可能有助于优化针对5-HT6的分子。
