Ab Initio Calculation of the Interaction Energy in the P2 Binding Pocket of HIV-1 Protease KANDA NIVESANOND, 1 ANIK PEETERS, 2 DIRK LAMOEN, 3 CHRISTIAN VAN ALSENOY 1 1 Department of Chemistry, University of Antwerp, Drie Eiken Campus, B-2610, Antwerp, Belgium 2 Tibotec BVBA, Gen. De Wittelaan L 11B 3, B-2800, Mechelen, Belgium 3 Department of Physics, University of Antwerp, Middelheim Campus, B-2020, Antwerp, Belgium Received 4 May 2005; accepted 19 May 2005 Published online 18 July 2005 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/qua.20724 ABSTRACT: Interactions at the P2 binding pocket of human immunodeficiency virus type 1 (HIV-1) protease have been studied using calculated interaction energies for model systems that mimic this binding pocket. Models were built for the P2 pocket of HIV-1 protease in complex with TMC114, nelfinavir, and amprenavir. A two-step procedure was applied. In the first step, the size of the model system was confined to 40 atoms, and the interaction energy was calculated at different computational levels. In the second step, the size of the system was increased to 138 atoms, and the calculations were only performed at the HF/6-31G** level. The interaction energy of the HIV-1 protease/TMC114 complex was found to be more favorable than the interaction energies of the other complexes because of the additional hydrogen bond interaction this inhibitor is able to make with the HIV-1 protease backbone. The results of the calculations are supported by stockholder charges and electrostatic potential maps. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem 105: 292–299, 2005 Key words: ab initio calculations; electrostatic potential map; HIV-1 protease; inhibitors; interaction energy; stockholder charges Introduction T he human immunodeficiency virus type 1 as- partyl protease (HIV-1 PR) is one of the major targets for anti-retroviral therapy [1–3]. HIV-1 PR has become the major target in the rational design of drugs for the treatment of HIV. A large number of HIV-1 PR inhibitors have been designed, some of which are used extensively in anti-HIV chemother- apy [4 –12]. Because of the mutations of HIV-1 PR, HIV-1 reverse transcriptase, and HIV-1 integrase, cross-resistance and multidrug resistance have been reported in HIV-infected patients on combi- nation therapy [13]. Therefore, novel inhibitors need to be more active against resistant variants of HIV-1. Consequently, the next-generation protease inhibitor TMC114 [Fig. 1(a)] has been developed. Correspondence to: C. Van Alsenoy; e-mail: kris.vanalsenoy@ua.ac.be Contract grant sponsor: IWT–Flemish Region. Contract grant number: IWT-161. Contract grant sponsor: University of Antwerp. Contract grant number: BOF UA/SFO UIA 2002. International Journal of Quantum Chemistry, Vol 105, 292–299 (2005) © 2005 Wiley Periodicals, Inc.