Statin Drugs mediate cholesterol levels by inhibiting the second step of the biosynthesis pathway. In this step, HMG-CoA is reduced to mevalonic acid by HMG-CoA reductase. Statin drug molecules displace the substrate HMG-CoA in the active site via competitive inhibition. While HMG-CoA takes advantage of hydrogen bonding, ion-dipole interactions and dispersion interactions to bind to HMG-CoA, statin drugs largely ignore dispersion interactions. We use correlated post-HF ab initio and several DFT methods to study these weak dispersion and induction interactions and we show that these interactions contribute to binding with similar weight as hydrogen bonds and ion-dipole interactions. We have identified a fragment which can take advantage of these weak interactions and we have attached this fragment to a statin drug molecule in order to create new drug candidates. We have docked these candidates in the active site and used ONIOM calculations to test the possible binding of these candidates to the enzyme. We believe that novel drug molecules that take advantage of these forces will be important in the next generation of statins.

Fragment based design of novel cholesterol moderating drugs using <i>ab initio</i> and DFT methods

239th National Meeting (2010)

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Fragment based design of novel cholesterol moderating drugs using ab initio and DFT methods