Theoretical Study On Generative Mechanism Of Reactive Metabolite And Structural Optimization Of Lapatinib

Lapatinib is an oral inhibitor of tyrosine kinase of epidermal growth factor receptor1（EGFR1）and EGFR2,which in combination with capecitabine is an efficacious therapy for advanced or metastatic breast cancer.However,it has been associated with idiosyncratic hepatotoxicity observed in clinical trials and post-marketing surveillance.Studies have shown that,at the chemical and cellular levels,idiosyncratic hepatotoxicity is associated with reactive metabolites.Therefore,it is especially important to understand the metabolic mechanism of Lapatinib.In this paper,we use density functional theory（DFT）to explore the metabolism of alkyl amine of Lapatinib catalyzed by cytochrome P450s（CYP450s,P450s）,including C₆-hydroxylation,C₈-hydroxylation,N₇-hydroxylation,as well as their downstream.The calculation results shown that oxidation of C₆ is the primary metabolic process and carboxylic acid is the main metabolic product.Both hydroxylation of C₈ and subsequent formation of primary hydroxylation amine are relatively feasible.However,it is not easy for the primary hydroxylation amine to form active metabolite nitroso by dehydration primary dihydroxylation amine,which indicates that there is other path for the production of nitroso.Carboxylic acid is not the main metabolite of N₇ oxidation because of higher hydrolysis energy barrier of intermediate nitrone.Meanwhile,the subsequent oxidation process of N₇ hydroxylation may be related to generation of nitroso.Therefore,apart from hydroxylation of C₈ forming primary hydroxylation amine（path A）,we designed other two paths related to the subsequent metabolism of N₇-hydroxylation:path B is the path of oxidation N₇-hydroxyl-Lapatinib forming nitrone,followed by hydrolysis nitrone,which can check the common proposed primary hydroxylation amine is metabolized by hydrolysis nitrone;path C is the path of dihydroxylation Lapatinib forming o-dihydroxy-Lapatinib subsequently decomposition.Both above two paths lead to the intermediate primary hydroxylation amine which indicates that primary hydroxylation amine is a critical metabolic intermediate for the nitroso formation.Calculation results show that it is difficult for Lapatinib to form primary hydroxylation amine via common proposed hydrolysis nitrone,while smoothly formed by path A and C with moderate determining step barriers.In addition,compared with dehydration primary dihydroxylation amine,it is easier to double hydrogen atom transfer（HAT）for primary hydroxylamine to form nitroso.The barrier of the latter is obviously lower than the former.Based on the above calculation results and drug structure analysis,several potential Lapatinib derivatives with decreasing toxicity were designed.Molecular docking results show that the binding pattern of these molecules to EGFR1 is similar to lapatinib.In terms of binding energy and binding efficiency,most compounds are potential to further research,especially,2a to 2d with similar binding energy to Lapatinib.The above work revealed the metabolic details of lapatinib which related to toxicity,and corresponding structural modifications.This work can enrich metabolic information of amine drugs and provide guidance for drug optimization and design.