Molecular Orbital Calculations and Nicotine Metabolism: A Rationale for Experimentally Observed Metabolite Ratios

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Abstract
The results of molecular orbital calculations and molecular modelling studies on nicotine are reported. It is shown that the product ratio of nicotine metabolism can be directly related to HOMO electron densities on the relevant hydrogen atoms associated with oxidation sites in S-nicotine. In addition, molecular modelling of nicotine within the putative active site of CYP2A6, the enzyme most closely associated with nicotine metabolism, indicates that the substrate is orientated for oxidation at the 5'-position via a combination of hydrogen bonding and pi-pi stacking interactions. Alternative routes of metabolism may require rotation of the pyrrolidine ring system and could, therefore, involve a degree of re-orientation of the nicotine molecule which is energetically less favourable than the modelled interaction indicating formation of cotinine via 5'-oxidation.