Development of Weiner et al. force field parameters suitable for conformational studies of [1,4]-benzodiazepines and related compounds.

A set of force field parameters capable of reproducing the preferred conformations of the biologically important [1,4]-benzodiazepines was developed for AMBER and other molecular modeling programs that utilize the Weiner et al. force field. Equilibrium parameters were obtained from representative model compounds found in the Cambridge Structural Database, and bond stretching and torsion potential force constants were estimated using AM1 and PM3 semiempirical Hamiltonians. Parameters obtained with the two semiempirical methods and the existing linear interpolation method are compared. Molecular mechanics and dynamic simulations showed that AM1 derived parameters, together with MNDO ESP fitted atomic charges, predicted the X-ray structure of a number of representative [1,4]-benzodiazepines within 0.01 A, 0.8 degree, and 5 degrees, from observed bond lengths, bond angles, and bond torsions, respectively.