MMPEN: Development and evaluation of penicillin parameters for Allinger's MMP2(85)programme

Abstract

A set of parameters, termed MMPEN, has been determined for the bicyclic nucleus of penicillin, which, in conjunction with the appropriate parameters from MMPEP and the internally stored parameters of the program, allow Allinger's force field and MMP2(85) program to be applied to the molecular mechanics treatment of penicillins. The MMPEN parameters are based on crystallographic heavy atom bond lengths and bond angles, vibrational spectra, and molecular orbital calculations. The parameters reproduce the experimental crystal structures of several penicillins, including penicillin G and penicillin V, with an average deviation of 0.005 Å in bond lengths, 0.5° in bond angles, and 3° in dihedral angles. Conformational analyses of penicillin G and penicillin V, for a dielectric constant, ε = 78.5 D suggest that neither penicillin retains the crystal structure in solution. In both cases, the global minima have the C3-carboxyl group antiperiplanar to the 2β-methyl group in the thiazolidine ring, and the side chains are oriented so that the amide N-H occupies the convex face of the molecule. The predicted conformations of the methyl esters of penicillin G and bisnorpenicillin G, for a dielectric constant of 4.8 D, are consistent with the nuclear magnetic resonance spectra obtained for these compounds in chloroform solvent.