Integrated ligand based pharmacophore model derived from diverse FAAH covalent ligand classes.
3D pharmacophore modeling is an important computational methodology for ligand-enzyme binding interactions in drug discovery. More specifically, a consensus pharmacophore model derived from diverse ligands is a key determinant upon which the prediction power of computational models is based for designing novel ligands. In this work, by merging the important pharmacophore features based on four classes of covalent FAAH ligands, and then integrating the exclusion volume spheres derived from the crystal structure, we created for the first time an integrated FAAH pharmacophore model to describe the ligand-enzyme binding interactions. This new integrated FAAH pharmacophore model can correctly predict the covalent ligand binding mode, which correlates with the SAR data. The study is expected to provide insights into novel covalent ligand-FAAH binding interactions, and facilitate the design of covalent ligands against FAAH.
Center for Drug Discovery, Northeastern University, Boston, MA 02115, USA.
Lingling
L
Shen
Hongwei
H
Huang
Alexandros
A
Makriyannis
Luke S
LS
Fisher
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D062126:Databases, Chemical; D015195:Drug Design; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D021621:Imaging, Three-Dimensional; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D008024:Ligands; D000099252:Fatty Acid Amide Hydrolases