Structural flexibility of non-nucleoside HIV-1 reverse transcriptase inhibitor: 9-Cl TIBO as explained by potential energy surface and (13)C and (1)H NMR calculations, based on ab initio and density functional study.

The conformational analysis of the HIV-1 reverse transcriptase inhibitor, (+)-(s)-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazol[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione or 9-Cl TIBO, has been investigated using high level of calculations, ab initio, and DFT theory. The potential energy surface as the function of two important rotatable dihedral angles of the 9-Cl TIBO side chain was generated by the Hartree-Fock method at the 3-21G basis set. Eight pronounced local minima were found to exist within an energy difference of less than 10 kJ/mol. The energy barriers between the different local minima are lower than 15 kJ/mol. A second derivative (frequency) analysis showed that all conformers are stable at this level of theory. These structures were used as starting points for full geometry optimizations at the HF/6-31G and B3LYP/6-31G levels of theory to obtain the absolute geometries and structural information. The comparisons of calculated conformers with the bound conformer in the X-ray structure were sequentially considered. Additionally, to obtain some structural information and to correlate between calculated structures and the structure in solution, NMR chemical shift calculations were also performed on all eight local minimum structures at B3LYP/6-311++G level, using the GIAO approach. The calculated (1)H NMR and (13)C NMR chemical shifts for the lowest energetic conformer give the greatest correspondence with the experimental results.