Miličević Ante, Šinko Goran
Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10 000 Zagreb, Croatia.
Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10 000 Zagreb, Croatia.
Eur J Pharm Sci. 2021 May 1;160:105757. doi: 10.1016/j.ejps.2021.105757. Epub 2021 Feb 12.
With the aging of the western population, more and more people are affected by the neurodegenerative Alzheimer's and Parkinson's disease. Inhibitors of acetylcholinesterase (AChE) have proven to be effective in the treatment of disease symptoms. We report the QSAR regression model for the estimation of potency of a set of 94 structurally diverse compounds (oximes, N-hydroxyiminoacetamides, 4-aminoquinolines and flavonoids) to inhibit AChE, pK (AChE). The model is based on three simple descriptors: the valence molecular connectivity index of the zero-order, χ, combined with the number of 10-membered rings (nR10) and number of hydroxyl groups in a molecule (nOH). QSAR model yielded r = 0.947, S.E. = 0.51 and S.E.= 0.53; the range of pK (exp) = 6.03. It showed its stability when the set of 94 compounds was enlarged, comprising 184 compounds in total (r = 0.886, S.E. = 0.85 and S.E. = 0.88; the range of pK (exp) = 10.21), resulting in regression parameters which were similar, although only for χ coefficients within the limits of S.E. (0.167(13) and 0.172(16) for the set with 94 and 184 compounds, respectively. The predictive power of the model was shown by the prediction of pK values for 61 randomly chosen compounds (S.E. = 0.86) from the calibration model made on the other 123 compounds (S.E. = 0.85), all taken from the pool of 184 compounds. QSAR descriptors χ, nR10 and nOH were well chosen for describing the interactions of the AChE active site (amino acid interaction) with ligands through the estimation of the inhibitory potency.
随着西方人口老龄化，越来越多的人受到神经退行性疾病阿尔茨海默病和帕金森病的影响。乙酰胆碱酯酶（AChE）抑制剂已被证明对治疗疾病症状有效。我们报告了一种定量构效关系（QSAR）回归模型，用于估算一组94种结构多样的化合物（肟、N-羟基亚氨基酰胺、4-氨基喹啉和黄酮类化合物）抑制AChE的效力，即pK（AChE）。该模型基于三个简单的描述符：零阶价分子连接性指数χ，结合分子中的十元环数量（nR10）和羟基数量（nOH）。QSAR模型得到r = 0.947，标准误差（S.E.）= 0.51和S.E. = 0.53；pK（实验值）范围为6.03。当94种化合物的集合扩大到总共184种化合物时，该模型显示出稳定性（r = 0.886，S.E. = 0.85和S.E. = 0.88；pK（实验值）范围为10.21），尽管仅χ系数在标准误差范围内相似（94种化合物的集合为0.167(13)，184种化合物的集合为0.172(16)）。通过对从校准模型中随机选择的61种化合物（S.E. = 0.86）的pK值进行预测，展示了该模型的预测能力，校准模型是基于另外123种化合物（S.E. = 0.85）建立的，所有这些化合物均来自184种化合物的集合。通过估算抑制效力，定量构效关系描述符χ、nR10和nOH被很好地选择用于描述AChE活性位点（氨基酸相互作用）与配体之间的相互作用。
