3D‐QSAR Studies on a Class of IKK‐2 Inhibitors with GALAHAD Used to Develop Molecular Alignment Models

Three‐Dimensional Quantitative Structure–Activity Relationship (3D‐QSAR) studies were preformed on a class of Ikb Kinase‐2 (IKK‐2) inhibitors, which contained thiophene‐carboxamide series and their analogs. Before 3D‐QSAR, a pharmacophore‐based molecular alignment model was built by using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Datasets (GALAHAD). At the same time, we constructed another molecular model by application of classical common structure alignment method as a comparative study. The results of the Comparative Molecule Field Analysis (CoMFA), the main 3D‐QSAR method applied in this paper, suggested that GALAHAD was a better tool for molecular alignment in this study. Based on the GALAHAD molecular alignment model, 3D‐QSAR analysis, including CoMFA and Comparative Molecule Similarity Indices Analysis (CoMSIA), was carried out. The leave‐one‐out cross‐validation correlation coefficient ( q _CoMFA² =0.642; q _CoMSIA² =0.675) and the good correlation between the predicted and experimental activities of excluded test compounds revealed that CoMFA and CoMSIA models were robust. These models are useful tools for predicting the inhibitory activities of the new compounds against IKK‐2. Suggestions of structural modification were then derived from the analysis of the 3D‐QSAR, and these will probably lead to the more active IKK‐2 inhibitors.