A critical challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophysical method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Q o site inhibitors of the cytochrome bc 1 complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (K i = 881.80 nM, porcine bc 1), the most potent compound 4f displayed 20 50...