C-1-02
Large-Scale Fragment Molecular Orbital Calculations
toward Evaluating the Drug Effects of AIDS Agents

12

Yoichiro Yagi 1,2

Yoshinobu Naoshima 1,2

yagi@sp.ous.ac.jp

naoshima@sp.ous.ac.jp

Institute of Natural Sciences, Okayama University of Science, 1-1 Ridai-cho,Kita-ku, Okayama 700-0005, Japan
Graduate School of Informatics, Okayama University of Science, 1-1 Ridai-cho,
Kita-ku, Okayama 700-0005, Japan

Keywords: HIV-1 protease, AIDS agent, drug effects, FMO calculation, quantum biology
In our continuous efforts to evaluate and predict the drug effects of currently approved HIV-1
protease inhibitors, we have carried out a large-scale fragment molecular orbital (FMO)
calculation at FMO-MP2/6-31G level on the complexes of HIV-1 protease with five different
peptidomimetic HIV-1 protease inhibitors such as Ritonavir (RTV), Indinavir (IDV), Nelfinavir(NFV), Darunavir (DRV), and Saquinavir (SQV) using ABINIT-MP/BioStation system [1-3]. In
addition, we performed the analogous FMO calculations toward four different complexes of reninand pepsin with RTV and SQV to explore a relationship between the computed energies and theunwanted side effects of HIV-1 protease inhibitors. Renin and pepsin are aspartic proteases andexist in human kidney and stomach, respectively. It has been reported that RTV gives acute renal
failure and severe gastrointestinal injury, while no renal toxicity is attributed to SQV.
FMO computations of five different inhibitor-bound HIV-1 protease complexes indicated thatthe calculated binding energy for the HIV-1 protease complexes can be correlated to the clinicallymeasured pharmacokinetic parameters such as maximum drug concentration (Cmax) and area
under the drug concentration-time curve (AUC) of the AIDS agents. We found that HIV-1 proteaseinhibitors having large values of Cmax and AUC such as RTV can strongly interact with HIV-1
protease, and that HIV-1 protease inhibitors with relatively large binding and interaction energies
can be highly effective as an AIDS agent [1-3]. When a drug was administered, it reaches its peaklevel in the blood. A drug travels through the blood to tissues in the body, is then metabolized andremoved from the blood. Cmax exhibits the highest drug level in the blood. AUC is universallyregarded as a measure of the extent of drug absorption. Although the reasons for the correlation of
the computed energy with Cmax and AUC are not clear, these two pharmacokinetic parameters
may be useful as indications for drug effects of AIDS agents [3]. For the human proteasecomplexes with RTV and SQV, the binding energy of RTV is larger than that of SQV. Furthermore,
it was found that the interaction energy of RTV with the active site aspartic acid in both humanproteases is large, while that of SQV with the active site is very small. We can safely say that thelarge interactions between the human proteases and RTV are implicated as a possible cause ofrenal dysfunction and severe gastrointestinal injury due to RTV inhibitor. Similar FMO4-MP2
calculations are under way to discuss the protease-inhibitor interactions in more detail.
[1] Yagi, Y., Iwasa, A., and Naoshima, Y., Large-Scale Quantum Chemical Calculation on theComplexes of HIV-1 Protease and Inhibitors: A Relationship of Calculation Energies with DrugEffects of Inhibitors, Proceedings of International Conference on Modeling and Simulation
Technology, JSST2011, JSST, 51-57, 2011.
[2] Yagi, Y. and Naoshima, Y., Large-Scale Quantum Chemical Calculations for the Drug Effects ofAIDS Agents, Abstracts of Joint Conference on Informatics in Biology, Medicine and Pharmacology
2012, C66_50, 2012[3] Yagi, Y., Hattori, Y., and Naoshima, Y., Large-Scale Quantum Chemical Calculation on theComplexes of HIV-1 Protease and Inhibitors: A Relationship of Calculation Energies with Drug
Effects of Inhibitors, Trans. Japan Soc. for Simulation Tech., 4(2):41-50, 2012.