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 c onformations of the biologically important [1,4]-benzodiazepines was d eveloped for AMBER and other molecular modeling programs that utilize the Weiner et al. force field. Equilibrium parameters were obtained fr om representative model compounds found in the Cambridge Structural Da tabase, and bond stretching and torsion potential force constants were estimated using AM1 and PM3 semiempirical Hamiltonians. Parameters ob tained with the two semiempirical methods and the existing linear inte rpolation method are compared. Molecular mechanics and dynamic simulat ions showed that AM1 derived parameters, together with MNDO ESP fitted atomic charges, predicted the X-ray structure of a number of represen tative [1,4]-benzodiazepines within 0.01 Angstrom, 0.8 degrees, and 5 degrees, from observed bond lengths, bond angles, and bond torsions, r espectively.