Comprehensive 3D-QSAR and binding mode of BACE-1 inhibitors using R-group search and molecular docking

• We study 3D-QSAR of BACE-1 inhibitors and their binding mode.
• We successfully design 30 new molecules with higher activity in theory.
• We find the inhibitors closely interact with 10 key sites of BACE-1.

The β-enzyme (BACE), which takes an active part in the processing of amyloid precursor protein, thereby leads to the production of amyloid-β (Aβ) in the brain, is a major therapeutic target against Alzheimer's disease. The present study is aimed at studying 3D-QSAR of BACE-1 inhibitors and their binding mode. We build a 3D-QSAR model involving 99 training BACE-1 inhibitors based on Topomer CoMFA, and 26 molecules are employed to validate the external predictive power of the model obtained. The multiple correlation coefficients of fitting modeling, leave one out cross validation, and external validation are 0.966, 0.767 and 0.784, respectively. Topomer search is used as a tool for virtual screening in lead-like compounds of ZINC databases (2012); as a result, we successfully design 30 new molecules with higher activity than that of all training and test inhibitors. Besides, Surflex-dock is employed to explore binding mode of the inhibitors studied when acting with BACE-1 enzyme. The result shows that the inhibitors closely interact with the key sites related to ASP93, THR133, GLN134, ASP289, GLY291, THR292, THR293, ASN294, ARG296 and SER386 of BACE-1.

The present study is aimed at studying 3D-QSAR of BACE-1 inhibitors and their binding mode based on Topomer CoMFA and molecular docking. We successfully design 30 new molecules with higher activity than that of all training and test inhibitors using Topomer search. The result shows that the inhibitors closely interact with the key sites related to ASP93, THR133, GLN134, ASP289, GLY291, THR292, THR293, ASN294, ARG296 and SER386 of BACE-1.Figure optionsDownload high-quality image (149 K)Download as PowerPoint slide