Convergent QSAR studies on a series of NK3 receptor antagonists for schizophrenia treatment

The dopamine hypothesis states that decreased dopaminergic neurotransmission reduces schizophrenia symptoms. Neurokinin-3 receptor (NK₃) antagonists reduce dopamine release and have shown positive effects in pre-clinical and clinical trials. We employed 2D and 3D-QSAR analysis on a series of 40 non-peptide NK₃ antagonists. Multivariate statistical analysis, PCA and HCA, were performed to rational training/test set splitting and PLS regression was employed to construct all QSAR models. We constructed one highly predictive CoMFA model (q^2?=?0.810 and r^2?=?0.929) and acceptable HQSAR and CoMSIA models (HQSAR q^2?=?0.644 and r^2?=?0.910; CoMSIA q^2?=?0.691, r^2?=?0.911). The three different techniques provided convergent physicochemical results. All models indicate cyclopropane, piperidine and di-chloro-phenyl ring attached to cyclopropane ring and also the amide group attached to the piperidine ring could play an important role in ligand–receptor interactions. These findings may contribute to develop potential NK₃ receptor antagonists for schizophrenia.     

定量计算萜类驱避化合物与二氧化碳缔合对其蚊虫驱避活性的影响

为验证萜类驱避化合物与嗅觉引诱物二氧化碳存在缔合作用, 并研究缔合作用对蚊虫驱避活性的影响。本研究借助计算化学的方法获得缔合体和缔合能量, 利用Gaussian View和Gaussian 03W软件分别构建和优化二氧化碳、 22个萜类蚊虫驱避化合物以及它们与二氧化碳缔合后的三维分子结构, 经Ampac 8.16转化后, 获得它们的缔合能量。借助定量构效关系计算方法研究缔合作用对驱避活性的影响, 利用Codessa 2.7.10计算获得驱避剂和缔合体的各类结构描述符, 从包括缔合体结构描述符及特征描述符在内的各类结构参数中筛选显著性参数, 以萜类驱避化合物对白纹伊蚊Aedes albopictus的校正驱避率的对数值为活性数据, 建立结构描述符与驱避活性的定量构效关系（quantitative structure-activity relationship, QSAR）模型。结果获得了22个萜类驱避化合物与二氧化碳缔合的缔合能量, 计算显示它们之间存在缔合作用并且可以形成缔合体; 获得1个R²为0.9643的4参数QSAR模型, 这4个参数所对应的结构描述符分别是COM-WNSA 3 Weighted PNSA (PNSA3*TMSA/1 000) ［Zefirov’s PC］, f-TerCO₂-Min e-n attraction for a C-O bond, M-Max 1-electron reaction index for an O atom, M-Min (>0.1) bond order of an H atom, 前2个参数分别为缔合体的整体结构描述符和碎片特征描述符。计算化学结果表明, 萜类驱避化合物与二氧化碳存在缔合作用, 该缔合作用对驱避活性的影响显著。     

3D QSAR studies on peroxisome proliferator-activated receptor γ agonists using CoMFA and CoMSIA

The peroxisome proliferator-activated receptors (PPARs) have increasingly become attractive targets for developing novel anti-type 2 diabetic drugs. We employed comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to study three-dimensional quantitative structure–activity relationship (3D QSAR) based on existing agonists of PPAR (including five thiazolidinediones and 74 tyrosine-based compounds). Predictive 3D QSAR models with conventional r² and cross-validated coefficient (q²) values up to 0.974 and 0.642 for CoMFA and 0.979 and 0.686 for COMSIA were established using the SYBYL package. These models were validated by a test set containing 18 compounds. The CoMFA and CoMSIA field distributions are in general agreement with the structural characteristics of the binding pockets of PPAR, which demonstrates that the 3D QSAR models built here are very useful in predicting activities of novel compounds for activating PPAR.      

曼地亚红豆杉对甲醛胁迫的生理响应

以一年生曼地亚红豆杉(Taxus media cv.hicksii)扦插苗为材料,采用密闭箱静态熏气法,研究不同甲醛（CH₂O）浓度(0、5、10、20和40 mg·m^-3)和熏气时间（1、3、5、7 d）对曼地亚红豆杉的生理响应。结果显示:（1）在5~20 mg·m^-3CH₂O浓度下,曼地亚红豆杉叶片均无受害症状,在40 mg·m^-3CH₂O熏气1 d时,叶片开始出现受害症状,并随时间的延长逐渐加重;（2）随着CH₂O浓度的增加和熏气时间的延长,叶片MDA、Pro含量和相对电导率皆呈增加趋势,SS含量表现为先升后降,但仍显著高于对照;（3）在5 mg·m^-3CH₂O处理下,叶片SOD、CAT、PPO和GR作为第一道防线共同作用以清除过多的活性氧,其中PPO最为敏感;在10、20 mg·m^-3CH₂O处理下,SOD、POD、CAT、PPO、APX和GR共同作用加快对活性氧的清理;在40 mg·m^-3CH₂O浓度下,各酶的活性均受到抑制,其中APX、PPO和GR活性显著低于对照,而SOD、POD和CAT活性仍显著高于对照。研究表明,在中低CH₂O浓度（5~20 mg·m^-3）处理下,曼地亚红豆杉主要通过合成渗透调节物质和活性氧自由基的酶促清除机制共同作用来适应逆境,在40 mg·m^-3CH₂O浓度下,APX、PPO、GR活性受到显著抑制,细胞膜过氧化程度加剧,植物叶片受到伤害;在CH₂O浓度低于20 mg·m^-3时,曼地亚红豆杉通过自身的应激保护系统来维持正常的生理活动,表现出较强的CH₂O耐受性。     

Design of novel quinazolinone derivatives as inhibitors for 5HT7 receptor

To study the pharmacophore properties of quinazolinone derivatives as 5HT₇ inhibitors, 3D QSAR methodologies, namely Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were applied, partial least square (PLS) analysis was performed and QSAR models were generated. The derived model showed good statistical reliability in terms of predicting the 5HT₇ inhibitory activity of the quinazolione derivative, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. This is evident from statistical parameters like q² (cross validated correlation coefficient) of 0.642, 0.602 and r² (conventional correlation coefficient) of 0.937, 0.908 for CoMFA and CoMSIA respectively. The predictive ability of the models to determine 5HT₇ antagonistic activity is validated using a test set of 26 molecules that were not included in the training set and the predictive r² obtained for the test set was 0.512 & 0.541. Further, the results of the derived model are illustrated by means of contour maps, which give an insight into the interaction of the drug with the receptor. The molecular fields so obtained served as the basis for the design of twenty new ligands. In addition, ADME (Adsorption, Distribution, Metabolism and Elimination) have been calculated in order to predict the relevant pharmaceutical properties, and the results are in conformity with required drug like properties.