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)

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 base d 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 v ariation of the two rotatable dihedral angles of the side chain was investi gated in detail, taking also into account the conformation of the seven-mem bered heterocyclic ring system. Several energy minima of comparable energy were found; they were compared to the conformation of the compound in the c rystal 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 surroundin g amino acids of the inhibition pocket shows that the conformation in the p ocket is close to an energy minimum conformation and the deviations are cau sed by the interaction with the complementary protein surface.