MP2, density functional theory, and semi-empirical calculations of the interaction energies between a series of statin-drug-like molecules and the HMG-CoA reductase active site Hunter E. Utkov, Allison M. Price, Mauricio Cafiero ⇑ Department of Chemistry, Rhodes College, 2000 North Parkway Memphis, TN, USA article info Article history: Received 19 October 2010 Received in revised form 3 February 2011 Accepted 6 April 2011 Available online 14 April 2011 Keywords: MP2 Ligand Protein Statin Drug design abstract In previous work [E.A. Kee, M.C. Livengood, E.E. Carter, M.L. McKenna, M. Cafiero, J. Phys. Chem. B 113 (2009) 14810] it has been shown that the residue Tyr479 in the active site of 3-hydroxy-3-methygluta- ryl-coenzyme A (HMG-CoA) reductase exerts a strong attraction on ligands. Statin drugs moderate blood cholesterol levels by acting as competitive inhibitors for this enzyme, blocking the biosynthesis of cho- lesterol early in the synthesis pathway. In this work a novel molecular fragment that binds strongly to Tyr479 has been developed using ab initio correlated methods and attached to known statin drugs (which bind well to other important residues in the active site) to create novel drug candidates that interact more strongly with the entire enzyme active site than the original drugs. Interaction energies between small molecule ligands and the target enzyme active site are calculated with all-electron density func- tional theory and semi-empirical methods, showing that the novel drug molecules will likely bind strongly in the active site. Solvation energies are also calculated to confirm behavior of the novel drug candidate molecules in vivo. Ó 2011 Elsevier B.V. All rights reserved. 1. Introduction As modern computational chemistry finds applications in larger and larger systems, methods which can be applied to these sys- tems in a reasonable amount of time and with a reasonable amount of resources are necessary. The study of protein–ligand interactions is just such a field that requires calculations on sys- tems of several hundreds of atoms—and potentially several thou- sands of electrons—at a time. One method that can be applied routinely to such systems is the ONIOM method [1]; in this method the system of interest—for example, a ligand bound to a protein ac- tive site—is divided into an upper level, which is to be treated with a high accuracy level of theory, and a lower level, which is to be treated with a lower accuracy level of theory. The portion of the system in the upper level may require correlated treatment, such as with Coupled Cluster (CC) or Density Functional Theory (DFT) calculations; the portion of the system in the lower level may re- quire a less demanding method, such as Hartree–Fock (HF; as demanding in computational resources as DFT, but without elec- tron correlation), a semi-empirical method, or even molecular mechanics. When a protein–ligand system features interactions between the ligand and the active site that depend largely on dis- persion and induction forces, care must be taken to use a modelling method for that particular portion of the system that treats disper- sion and induction well. While many dipole–dipole interactions that typically dominate protein–ligand systems can have energies between 5 and 20 kcal/mol, induction and dispersion interactions can have energies under 5 kcal/mol, thus requiring greater overall accuracy when computing. This work examines an interesting and timely study of a system—statin drugs bound to their target en- zyme—that requires careful treatment of dispersion and induction. Interaction energies between the drugs and the enzyme active site are calculated using DFT and semi-empirical methods. The DFT cal- culations show interesting detail regarding the interaction charac- teristics of the stain-like drug molecules. The class of cholesterol moderating drugs commonly called sta- tin drugs work by inhibiting the second step in the biosynthetic pathway that ultimately leads to the production of cholesterol. Statins do this by binding to the active site of the enzyme, 3-hydro- xy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase, therefore blocking the natural substrate HMG-CoA (see Fig. 1) and disabling the synthesis of cholesterol. Current statin drugs are considerably smaller than the natural substrate HMG-CoA and bind to a small section of the HMG-CoA reductase active site, primarily to four res- idues: Asp690, Lys691, Lys692, and Ser684 (see Fig. 2 for interac- tions between these four residues and the HMG moiety of HMG- CoA). The crystal structure work of Istvan and Deisenhofer [2] 2210-271X/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.comptc.2011.04.013 ⇑ Corresponding author. Tel.: +1 901 843 3955. E-mail address: cafierom@rhodes.edu (M. Cafiero). Computational and Theoretical Chemistry 967 (2011) 171–178 Contents lists available at ScienceDirect Computational and Theoretical Chemistry journal homepage: www.elsevier.com/locate/comptc