Theoretical Study On The Metabolic Mechanisms Of Dimethylxanthine Alkaloids And Chlorpromazine

Theobromine and theophylline, belonging to the dimethylxanthine alkaloids, are very important psychotropic drugs to excite central nervous system. Theobromine displays application as a diuretic and tracheal smooth muscle relaxant and has the functions of vasodilatation and myocardial stimulation. Theophylline can relax the muscle of the bronchus and expand the peripheral vascular, and is used for the treatments of asthma and chronic obstructive pulmonary disease in medicine. Chlorpromazine which belongs to aliphatic phenothiazines, is an important antipsychotic. However, some serious side effects(some even irreversible) are emerged after excessive and long-term intake of these drugs. The metabolic processes of these drugs remain elusive up to now, which results in the stagnation in the studies metabolites and side effects. Therefore, the metabolic mechanisms of theobromine, chlorpromazine and theophylline have been systematically explored in this paper based on quantum chemical methods in help of providing theoretical information for the further studies on the medical pharmacological effects and side effects.First, the main metabolic mechanism of theobromine, N-demethylation, catalyzed by P450 isoenzyme 1A2(CYP1A2) was studied using density functional theory(DFT). Two N-demethylation pathways were characterized, i.e., N3- and N7-demethylations, which involve the initial N-methyl hydroxylation to form carbinolamine complexes and the subsequent carbinolamines decomposition to yield monomethylxanthines and formaldehydes. The calculated results have shown that the rate-limiting N-methyl hydroxylation occurs via a hydrogen atom transfer(HAT) mechanism, which proceeds in a spin-selective mechanism(SSM). From the viewpoint of thermodynamics and kinetics, N3-demethylation is more favorable than N7-demethylation due to its lower free energy barrier and 7-methylxanthine therefore is the optimum product reported for the demethylation of theobromine catalyzed by CYP1A2, which are in good agreement with the experimental observation. The carbinolamines generated are prone to decomposition via the contiguous heteroatom-assisted proton-transfer.And then, the metabolic mechanism of chlorpromazine catalyzed by CYP1A2 was determind at the theoreticl level. Three types of metabolic mechanisms were characterized, including S5-oxidation, aromatic hydroxylation, and N-demethylation. The calculated results demonstrate that N14-demethylation is the most favorable metabolic pathway of chlorpromazine due to its lowest energy barrier, followed by S5-oxidation. Then, mono-N-demethylchlorpromazine is the most feasible chlorpromazine metabolite, which can proceed further demethylation to form di-N-desmethyl-chlorpromazine. Besides, chlorpromazine 5-sulfoxide and 7-hydroxy-chlorpromazine are both the possible metabolites of chlorpromazine. Interestingly, N-methyl hydroxylation, the rate-limiting step of N-demethylation, proceeds predominantly via a single electron transfer(SET) mechanism. All the proton transfer processes involved in the aromatic hydroxylation and N-dealkylation prefer to occurrence in a water-assisted enzymatic process. Each metabolic pathway proceeds in the spin-selective manner(SSM), mainly via the LS state of Cpd I.Finally, the methylation mechanisms of theophylline catalyzed by xanthine methyl transferase(XMT), were identified by density functional theory. Two types of metabolic mechanisms were characterized, including keto-reaction and O6-enol-reaction mechanisms. In order to investigate the roles of the significant residues Gln161, Asn25, Tyr321, Trp162 and Tyr356 on the methylation reaction, nine types of reaction models were established for each mechanism, which contain different species and various numbers of residues. The calculated results suggest that O6-enol-reaction mechanism is thermodynamically and kinetically more favorable than keto-reaction mechanism due to its lower energy barrier. Residue Gln161 has important role in the methylation process, since its amide oxygen atom can capture the lost proton of theophylline. The other four residues at the activity center have stabilizing effect and spatial orientation interaction. Compared to residues Tyr321, Trp162 and Tyr356, residue Asn25 show the most important role on the stability of the reation center. The amide oxygen and amide hydrogen of Asn25 can form strong hydrogen bonds with the C8-H and N9 atoms of theophylline, respectively, which increases the negativity of N7 atom and facilitates the methyl group transfer, leading to the obvious decrease of activation energy. This work has revealed the detail methylation mechanisms of theophylline and evaluated the important roles of residues(Gln161, Asn25, Trp162 and Tyr356) in the catalytic process.