Discovery and development of statins polar methane sulfonamide group, which is quite hydrophilic and confers low lipophilicity. The sulfonamide group forms a unique polar interaction with the enzyme. As a result, rosuvastatin has superior binding affinity to the HMGR enzyme compared to the other statins, which is directly related to its efficiency to lower LDL cholesterol. Lipophilicity of the statins is considered to be quite important since the hepatoselectivity of the statins is related to their lipophilicity. The more lipophilic statins tend to achieve higher levels of exposure in non-hepatic tissues, while the hydrophilic statins tend to be more hepatoselective. The difference in selectivity is
Discovery and development of statins that the statins exploit and is used to accommodate their hydrophobic moieties. The specificity and the tight binding of statins is due to orientation and bonding interactions that form between the statin and the HMGR enzyme. Polar interactions are formed between the HMG-moiety and residues that are located in the cis loop of the enzyme. These polar interactions are between Ser, Asp, Lys and Lys (Figure 4). The terminal carboxylate of the HMG moiety forms a salt bridge with the cationic Lys of the enzyme. In addition to the polar interaction, Lys participates in a hydrogen bonding network with Glu,