Cheminformatics is used to validate the capabilities of widely used quantum chemistry and molecular mechanics methods. Among the quantum methods examined are the semiempirical MNDO, AM1, and PM3 methods, Hartree-Fock (ab initio) at a range of basis set levels, density functional theory (DFT) at a range of basis sets, and a post-Hartree-Fock method, local Moller-Plesset second-order perturbation theory (LMP2). Among the force fields compared are AMBER, MMFF94, MMFF94s, OPLS/A, OPLS-AA, Sybyl, and Tripos. Programs used are Spartan, MacroModel, SYBYL, and Jaguar. The test molecule is (2-amino-5-thiazolyl)-alpha-(methoxyimino)-N-methylacetamide, a model of the aminothiazole methoxime (ATMO) side chain of third-generation cephalosporin antibacterial agents. The Ward hierarchical clustering technique yields an insightful comparison of experimental (X-ray) and calculated (energy optimized) bond lengths and bond angles. The computational chemistry methods are also compared in terms of the potential energy curves they predict for internal rotation. Clustering analysis and regression analysis are compared. The MMFF94 force field such as implemented in MacroModel is the best overall computational chemistry method at reproducing crystallographic data and conformational properties of the ATMO moiety. This work demonstrates that going to a higher level of quantum theory does not necessarily give better results and that quantum mechanical results are not necessarily better than molecular mechanics results.

Baertschi et al. (Antiviral Chem. Chemother. 1997, 8, 353-362) clarified the nature of a polymeric degradation product formed from the cephalosporin ceftazidime. Interest in the polymeric material arises from its ability to inhibit the RNase H and polymerase activities of HIV-1 reverse transcriptase (RT). To shed light on the structure of the polymeric material like that which forms from degradation of third-generation cephalosporins, we apply molecular modeling and other computational chemistry techniques. Aminothiazole methoxime (2-amino-4-thiazolyl-methoxyimino; ATMO) is the parent structure related to the isolated degradation product of ceftazidime. The MMFF94 force field and Monte Carlo multiple minimum method as implemented in MacroModel are used to generate low-energy conformers. We built up oligomeric models starting from the trimer to the 16-mer and performed distribution analyses on the dihedral angles from the Monte Carlo runs to analyze the three-dimensional shapes of the oligomers. Although the larger oligomers are too long for a complete search of conformational space, the low-energy conformers examined do not show secondary structure or repetitive conformations. Polymeric ATMO material may, therefore, exhibit only random coil conformations. Topological similarity of ATMO structures to other reported RT inhibitors is also examined.

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