Large-Scale Quantum Chemical Calculation on the Complexes of HIV-1 Protease and Inhibitors: A Relationship of Calculation Energies with Drug Effects of Inhibitors

Abstract

  We have carried out a large-scale biomolecular quantum chemical computation on the complexes of HIV-1 protease with six different peptidomimetic HIV-1 inhibitors by employing the ab initio fragment molecular orbital (FMO) method at MP2/6-31G calculation level, in order to clarify a relationship between the computed binding energy ΔE for the HIV-1 protease complexes and the clinically measured pharmacokinetic parameters such as maximum drug concentration (Cmax) and area under the drug concentration-time curve (AUC), both of which may be used as indications for drug effects of HIV-1 inhibitors. The FMO calculations indicate that the inhibitor bearing a negatively large binding energy has relatively large values of Cmax and AUC. In addition, similar FMO computations on the complexes of a human protease renin with two HIV-1 protease inhibitors, Ritonavir and Saquinavir, show that the binding energy for Ritonavir with many side effects is negatively larger than that for Saquinavir with few side effects.