Despite the availability of many reliable in silico approaches and robust in vitro commercially available assays, discovering BACE-1 inhibitors still remains a challenging task. In the present study, based on the virtual screening of 10,000 compounds of training set, the PCA approach yielded consistently superior rankings compared to conventional consensus scoring and single scoring. By virtual screening of 113,228 compounds, and application of PCA approach to re-rank the score list, two drug like BACE-1 inhibitors were emerged as an effective low-micromolar inhibitors. It suggested that the application of PCA provides a more robust strategy for ranking compounds. The advantages of PCA are as follows.