Computational study of the interaction between TIBO inhibitors and Y181 (C181), K101, and Y188 amino acids.

The non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are an important class of drugs employed in anti-HIV chemotherapy. TIBO compounds, which belong to the NNRTIs class, are potent inhibitors of the HIV-1 reverse transcriptase enzyme (HIV-1 RT). However, mutations in the amino acids present in the active site of these inhibitors limit their clinical use. In this work, the intermolecular interactions taking place between compounds of the TIBO family and Y181 (C181), K101, and Y188 amino acids are investigated. For this purpose the coordinates of three RT crystalline structures complexed with TIBO were taken from PDB database, and were analyzed by means of the B3LYP/6-31+G(d,p) model. The natural bond orbital (NBO) and atoms in molecules (AIM) methods indicate that not only does the Y181C mutation lead to loss of favorable interactions between the TIBO side chains and tyrosine, but it also affects the interaction between the inhibitor and K101 and Y188. Results also revealed that the interaction between TIBO and K101 is stabilized by N-H...O and N-H...S hydrogen bonds. This is the first time that the presence of the latter hydrogen bond (N-H...S) is reported to play an important role in the stabilization of the interaction between TIBO and K101. In addition the NBO and natural population analyses (NPA) indicate that the 8 Cl-TIBO inhibitor presents a more effective interaction with the Y181, K101, and Y188 than that of 9 Cl-TIBO.