Molecular Calculations on the Conformation of the HIV-1 Reverse Transcriptase Inhibitor (+)-(S)-4,5,6,7-Tetrahydro-8-chloro-5-methyl-6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk][1,4] benzodiazepine-2(1H)-thione (8-Chloro-TIBO)

Summary.

 The conformational analysis of the HIV-1 reverse transcriptase inhibitor (+)-(S)-4,5,6,7-tetrahydro-8-chloro-5-methyl-6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione (8-chloro-TIBO) was performed based on ab initio (HF/3‐21G, HF/6‐31G(d,p)) as well as on DFT (B3LYP/6‐31G(d,p)) calculations. The potential energy surface of the molecule obtained by variation of the two rotatable dihedral angles of the side chain was investigated in detail, taking also into account the conformation of the seven-membered heterocyclic ring system. Several energy minima of comparable energy were found; they were compared to the conformation of the compound in the crystal structure of the inhibition complex with HIV-1 RT. The comparison of the calculated energy minimum conformations with the crystal structure and the determination of the distances between the molecule and the surrounding amino acids of the inhibition pocket shows that the conformation in the pocket is close to an energy minimum conformation and the deviations are caused by the interaction with the complementary protein surface.