Theoretical studies of the reactivity of the anthracycline family of drugs will be undertaken using the AM1 formalism. The thrust of these studies is to gain insight from quantum chemistry/pharmacology, molecular modeling and statistical inference to understand molecular-level features that govern chemical reactivity but are concealed by the molecular structure and raw experimental data (Ref. 40). Tautomers, radicals/biradicals, possible intermediates and metabolites, metal complexes, etc. will be examined. Optimized geometries will be obtained and the relative stabilities will be determined on the basis of charge distribution, molecular orbital structures, etc. Relative reactivities will be probed using calculated molecular orbital energies (of HOMO, LUMO, SOMO). The origins of the relative stabilities and reactivities will be examined by energy- partitioning analysis. The computed electronic properties will be used, along with available experimental data, for QSAR/CoMFA studies to develop structure/activity (S/A) relationships. The S/A relationships developed this way will in turn be used to predict the biological activity of theoretical models - not-yet-synthesized drugs. Other studies will include reaction profiles/surfaces of models for formation of metabolites, conformational searches/minimum energy path calculations, transition state location, electron transfer reactions (metal to ligand and vice versa) by Mulliken population analysis, etc.
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