S-Oxidation is an important cytochrome P450 (CYP450)-catalyzed reaction, and the structural and energetic details of this process can only be studied by using quantum chemical methods. Thiazolidinedione (TZD) ring metabolism involving initial S-oxidation leads to the generation of reactive metabolites (RMs) and subsequent toxicity forcing the withdrawal of the glitazone class of drugs, thus, the study of the biochemical pathway of TZD ring metabolism is a subject of interest. The S-oxidation of the TZD ring and the formation of the isocyanate intermediate (ISC) was implicated as a possible pathway; however, there are several questions still unanswered in this biochemical pathway. The current study focuses on the CYP450-mediated S-oxidation, fate of the sulfoxide product (TZDSO), ring cleavage to ISC, and formation of nucleophilic adducts. The process of S-oxidation was explored by using Cpd I (iron(IV)-oxo porphyrin, to mimic CYP450) at TZVP/6-311+G(d) basis set. The barriers were calculated after incorporating dispersion and solvent corrections. The metabolic conversion from TZDSO to ISC (studied at B3LYP/6-311++G(2df,3pd)//B3LYP/6-31+G(d)) required a novel protonated intermediate, TZDSOH(+). The effect of higher basis sets (6-311+G(d,p), aug-cc-pvqz) on this conversion was studied. TZDSOH(+) was observed to be more reactive and thermodynamically accessible than ISC, indicating that TZDSOH(+) is the actual reactive intermediate leading to toxicity of the TZD class of compounds.

Cytochrome P450 (CYP450)e nzymes play important roles in maintaining human health andt heir reaction rates are dependento nt he first electron transfer from the reduction partner.I nterestingly,e xperimental work has shown that this step is highly influenced by the addition of metal ions. To understand the effect of externalp erturbations on the CYP450 first reduction step, we have performed ac omputational studyw ith model complexes in the presence of metal and organic ions, solvent molecules, and an electricf ield. The results show that these medium-rangei nteractions affect the driving force as well as electron-transfer rates dramatically.Based on the location, distance, and direction of the ions/electric field, the catalytic reaction rates are enhanced or impaired. Calculations on al arge crystal structure with bonded alkali metal ions indicated inhibition patterns of the ions. Therefore, we predict that the activef orms of the naturalC YP450i sozymes will not have more than one alkali metal ion bound in the second-coordination sphere. As such, this study provides an insighti nto the activity of CYP450 enzymes and the effects of ions and electric field perturbations on their activity.

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