TY - JOUR
T1 - A combined QM/MM approach to protein-ligand interactions
T2 - Polarization effects of the HIV-1 protease on selected high affinity inhibitors
AU - Hensen, Christian
AU - Hermann, Johannes C.
AU - Nam, Kwangho
AU - Ma, Shuhua
AU - Gao, Jiali
AU - Höltje, Hans Dieter
PY - 2004/12/30
Y1 - 2004/12/30
N2 - HIV-1 protease inhibitors are one of the two widely used therapeutic agents for the treatment of HIV-infected patients. The investigation of HIV-1 protease-inhibitor interactions can provide further insight for developing new compounds that are still required due to the growing problem of drug resistance. To this end, a combined QM/MM approach was used to determine electrostatic and polarization interactions on three high affinity inhibitors, nelfinavir, mozenavir, and tipranavir. The present computational results show that explicit treatment of the polarization effect is particularly important since it can contribute as much as one-third of the total electrostatic interaction energy. Further, an amino acid decomposition analysis was applied to determine contributions of individual residues to the enzyme-inhibitor interactions. It was found that the 4-hydroxy-dihydropyrone substructure of tipranavir is especially suited for extended charge delocalization by interacting with the catalytic aspartates and isoleucines of the HIV-1 protease. The calculated electron density difference maps reaffirm and provide a means of visualizing these results.
AB - HIV-1 protease inhibitors are one of the two widely used therapeutic agents for the treatment of HIV-infected patients. The investigation of HIV-1 protease-inhibitor interactions can provide further insight for developing new compounds that are still required due to the growing problem of drug resistance. To this end, a combined QM/MM approach was used to determine electrostatic and polarization interactions on three high affinity inhibitors, nelfinavir, mozenavir, and tipranavir. The present computational results show that explicit treatment of the polarization effect is particularly important since it can contribute as much as one-third of the total electrostatic interaction energy. Further, an amino acid decomposition analysis was applied to determine contributions of individual residues to the enzyme-inhibitor interactions. It was found that the 4-hydroxy-dihydropyrone substructure of tipranavir is especially suited for extended charge delocalization by interacting with the catalytic aspartates and isoleucines of the HIV-1 protease. The calculated electron density difference maps reaffirm and provide a means of visualizing these results.
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U2 - 10.1021/jm0497343
DO - 10.1021/jm0497343
M3 - Article
C2 - 15615516
AN - SCOPUS:11144235131
SN - 0022-2623
VL - 47
SP - 6673
EP - 6680
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 27
ER -