Structural features of GABAA receptor antagonists: pharmacophore modeling and 3D-QSAR studies

• DOI: 10.1007/s00044-013-0583-7
• Publication Date: 2013-03-30T06:25:46Z
• Authors: Wei Zhang; Shuang Xia; Jinjin Ye; Yun Tang; Zhong Li; Weiping Zhu; Jiagao Cheng
• Keywords: Molecular model

Pharmacophore modeling, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) studies have been carried out on 5-(4-piperidyl)-3-isoxazolol (4-PIOL) analogs as GABAA receptor antagonists in this study. The best pharmacophore hypothesis generated by PHASE was ADHPR.6, which comprised a hydrogen bond acceptor (A), a hydrogen bond donor (D), a hydrophobic group (H), a positively charged group (P), and an aromatic ring (R). The pharmacophore model provided a good alignment for the further 3D-QSAR analyses, which presented a good R 2 value of 0.943, 0.930, and 0.916 for atom-based QSAR model, CoMFA model, and CoMSIA model, respectively. All QSAR models presented good statistical significance and predictivity, the corresponding Q 2 values for each 3D-QSAR model are 0.794, 0.569, and 0.637, respectively. Both pharmacophore and CoMSIA results showed that the hydrophobic sites are the key structural feature for GABAA receptor antagonists with high activities.