A search for quantum mechanical methods suitable for the conformational analysis of models related to some inverse agonists of the benzodiazepine receptor

The target of this work consists in a search, among several methods of quantum mechanical calculations, for the most suitable one (both with regard to accuracy and speed) for doing conformational analysis on models related to molecules belonging to a group of indol-3-yl glyoxylyl derivatives, many of which behave as ligands of the benzodiazepine receptor (BzR). Among the wide variety of ligands of the BzR, β-carboline derivatives are included, many of which show a pharmacological profile similar to the one exhibited by compounds of interest to us. A structure analogy between our compounds and β-carboline derivatives could be hypothesized, depending upon the preferred arrangement of the investigated molecules with respect to the dihedral angles of the indol glyoxylyl moiety. Therefore a potential energy surface scan has been carried out on selected models either by the quantum mechanical semiempirical methods MNDO, AM1, PM3 (by using the programs included in the mopac package) or by a quantum mechanical SCF ab initio method (by using the gaussian-80 program), both in order to find support for the choice of the more suitable semiempirical method, and in order to verify a structural analogy between our compounds and the β-carboline ring. The results showed that AM1 and PM3, unlike MNDO, seem to be suitable semiempirical methods for doing potential energy surface scans on this kind of molecule. The preferred arrangement showed by the models with respect to the indol glyoxylyl moiety appeared to support the hypothesis about the structure analogy between the investigated ligands and β-carboline derivatives