Drug-metabolizing enzymes,also known as cytochrome P450s,are a superfamily of hemoglobin responsible for metabolizing more than 90% clinical drugs.Cytochrome P450 2D6(CYP2D6) is a significant member of cytochrome P450s for the reason of metabolizing about 20% clinical drugs.In this paper,molecular docking and molecular dynamic simulations are used to investi-gate the active site of CYP2D6,roles of essential amino acids within the active site and time-dependent protein energy changes.The results suggest that amino acids Glu216,Asp301,Ser304 and Ala305 in the active site are likely to form hydrogen bonding interactions with substrates;the benzene ring of Phe120 and aromatic ring in the substrates form Π-Π interactions.In addition,molecular dynamics simulations prove that the catalytic conformation of CYP2D6 without ligands can be obtained by their own atomic fluctuations.The impact of ligands on protein system energy and large conformational shift is not very large.Cytochrome P450s is known for their genetic polymorphisms,which will result in severe adverse drug reactions.Ideally,we hope to use mo-lecular modeling to investigate the differences between the substrates of wild-type and mutants while they are bonded with drugs,and predict the drug metabolizing ability of mutants.Reduce the possibility for people taking drugs that they can not metabolize,therefore reduce the rate of adverse drug reactions,and eventually establish a platform of personalized drugs to largely benefit human health. Drug-metabolizing enzymes, also known as cytochrome P450s, are a superfamily of hemoglobin responsible for metabolizing more than 90% of clinical drugs. Cytochrome P450 2D6 (CYP2D6) is a significant member of cytochrome P450s for the reason of metabolizing about 20% of clinical drugs. In this paper, molecular docking and molecular dynamics simulations are used to investi-gate the active site of CYP2D6, roles of essential amino acids within the active site and time-dependent protein energy changes. The results suggest that amino acids Glu216, Asp301, Ser304 and Ala305 in the active site are likely to form hydrogen bonding interactions with substrates; the benzene ring of Phe 120 and aromatic rings in the substrates form Π-Π interactions. In addition, molecular dynamics simulations prove that the catalytic conformation of CYP2D6 without ligands can be obtained by their own atomic fluctuations. The impact of ligands on protein system energy and large conformational shift is not very large. Cytochrome P450s is known for their genetic polymorphisms, which will result in severe adverse drug reactions. Ideally, we hope to use mo-lecular modeling to investigate the differences between the substrates of wild-type and mutants while they are bonded with drugs, and predict the drug metabolizingizing ability of mutants.Reduce the possibility for people taking drugs that they can not metabolize, therefore reduce the rate of adverse drug reactions, and ultimately establish a platform of personalized drugs to substantially benefit human health.