Abstract: P-glycoprotein 1 (Pgp), also called multidrug resistance protein 1 (MDR1), is one of the most widely dispersed and effective transporters found in cancer resistances. This research works sought to use computational methods to understand structure and functional relationship using the binding energies and structural similarity of the lowest binding molecules. A series of 479 molecules including alkaloids, flavinoids, cyclic imides, lactams, lactones, NSAIDS, sulfanilamides, and known Pgp binders were bound to 3 Pgp crystal structures (35GU, 3G60, 3G61) . Computational results matched that of experimental result with a group of current pharmaceuticals which include Digoxin, Etoposide, Tacrolimus, and Paclitaxel maintaining the lowest energy (averaged over the three proteins). Similarity searches of the lowest binding molecules were conducted to determine important structural motifs. This research allows a better understanding of drug interaction towards the blockade of the function of Pgp.