Abstract: Design and optimization of efficient green flotation collectors will be the hot and difficult points in the future flotation process strengthening. Given the chemical structure characteristics that many oxygenated sites exist on difficult-to-float coal surface, this paper introduced the molecular docking technology which is widely used in the field of biomedicine into the virtual screening of collectors for difficult-to-float coal. The molecular docking results between a variety of collectors and difficult-to-float coal were explored, the correlativity between the molecular docking and the flotation results was analyzed, and the guiding role of molecular docking on flotation collectors screening was revealed. The same regular pattern of molecular docking was found betweenthe collectors and No.1, No.6, No.7, and No.8 oxygenated active sites as well as thewhole coal molecule. Global docking and local docking verify each other, i.e., the absolute value of the binding energiesfollow the same order:dodecane