Inhibitory mode of indole-2-carboxamide derivatives against HLGPa: molecular docking and 3D-QSAR analyses.
The interaction of a series of indole-2-carboxamide compounds with human liver glycogen phosphorylase a (HLGPa) have been studied employing molecular docking and 3D-QSAR approaches. The Lamarckian Genetic Algorithm (LGA) of AutoDock 3.0 was employed to locate the binding orientations and conformations of the inhibitors interacting with HLGPa. The binding models were demonstrated in the aspects of inhibitor's conformation, subsite interaction, and hydrogen bonding. The very similar binding conformations of these inhibitors show that they interact with HLGPa in a very similar way. Good correlations between the calculated interaction free energies and experimental inhibitory activities suggest that the binding conformations of these inhibitors are reasonable. The structural and energetic differences in inhibitory potencies of indole-2-carboxamide compounds were reasonably explored. Using the binding conformations of indole-2-carboxamides, consistent and highly predictive 3D-QSAR models were developed by CoMFA and CoMSIA analyses. The q2 values are 0.697 and 0.622 for CoMFA and CoMSIA models, respectively. The predictive ability of these models was validated by four compounds that were not included in the training set. Mapping these models back to the topology of the active site of HLGPa leads to a better understanding of the vital indole-2-carboxamide-HLGPa interactions. Structure-based investigations and the final 3D-QSAR results provide clear guidelines and accurate activity predictions for novel inhibitor design.
Liu
Guixia
G
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
Zhang
Zhenshan
Z
Luo
Xiaomin
X
Shen
Jianhua
J
Liu
Hong
H
Shen
Xu
X
Chen
Kaixian
K
Jiang
Hualiang
H
D001665:Binding Sites; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D006801:Humans; D006860:Hydrogen Bonding; D021621:Imaging, Three-Dimensional; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D021281:Quantitative Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007211:Indoles; D024981:Glycogen Phosphorylase