The microtubule-associated Tau protein aggregates into insoluble paired helical filaments (PHFs) that deposit as neurofibrillary tangles (NFTs) which may cause neurodegeneration in brains of those with Alzheimer’s disease (AD) and other related tauopathies; therefore, the drug discovery targeting on Tau protein has attracted an increasing number of researchers. In the last decade, most of the studies were focused on the approach to search for inhibitors of phosphorylation kniases, while only few put their eyes on the approach to discover inhibitors of Tau self-aggregation process. Phenylthiazolyl-Hydrazide (PTH) with the same core structure is a kind of molecules that directly inhibit Tau self-aggregation process. To illuminate the relationship between the structure of R-groups and molecular activities, and design new molecules with higher activity than the template molecule, topomer CoMFA was employed in three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of 26 phenylthiazolyl-hydrazides (PTH) derivatives as Tau protein inhibitors. The Topomer CoMFA model has good fitting ability and predictive ability. The number of principal components, r2,q2, rpred.2, SEE and F of the Topomer CoMFA model were 5, 0.976, 0.603, 0.795, 0.110 and 115.778, respectively. The model was used to search R-groups with special activity contribution from ZINC database. By No.1 molecule filtering, there were 9 R1-groups and 2 R2-groups with contribution values rising by 20%. We employed the 9 R1-groups and 2 R2-groups to alternately substitutes for the R1 and R2 of sample 1; as a result, we got a total of 18 new compounds and further predicted their activities using the Topomer CoMFA model obtained, and the activity of 15 of them were higher than that of the template molecule. This research showed that Topomer search could be effectively used in molecular design; meanwhile, the molecules designed provide new candidate drugs for drug development of Alzheimer’s disease.
