Systematic investigation on the binding of GW420867X as HIV-1 reverse transcriptase inhibitor

作者：Saparpakorn Patchreenart^*; Wolschann Peter; Karpfen Alfred; Pungpo Pornpan; Hannongbua Supa

来源：Monatshefte fur Chemie, 2011, 142(9): 961-971.

DOI：10.1007/s00706-011-0497-3

• NNRTI
• HIV-1 RT
• MP2
• M06-2X
• Interaction energy

The interactions between ligands and the surrounding binding site depend on the different contributions of individual amino acids. The determination of these particular interaction energies is sensitive to the model used, i.e., which part of the amino acids is taken into account and which terminating procedure is applied. In this study, the subtle interaction between individual residues from the HIV-1 reverse transcriptase allosteric binding site and an inhibitor, isopropyl (S)-2-ethyl-7-fluoro-3,4-dihydro-3-oxoquinoxalin-1(2H)-carboxylate (GW420867X), was investigated by using high-level quantum chemical calculations (MP2, M06-2X, and B3LYP) with the following basis sets: 6-31G(d), 6-31G(d,p), 6-311G(d), and 6-311G(d,p). The results obtained indicate that the interaction between the inhibitor and Lys101 is the most important one for the binding. We have calculated this interaction using various models to evaluate the effect of neighboring residues. Electrostatic interactions induced by the terminating substituents were also studied using natural population analysis. The results show that even systems where the amide bond is cut and capped with hydrogen atoms can be used as reliable models for estimating the individual interaction energies. Furthermore, the interaction energies of GW420867X in wild-type and Lys101Glu mutant are also investigated to explain the loss of GW420867X's activity in the Lys101Glu mutant.

• 出版日期2011-9