Rosiglitazone Metabolism: A Molecular modeling study using PM6 Model

Molecular Modelling studies based on molecular mechanics and semi-empirical methods have been carried out for RGT and its metabolites in order to gain insight into excretion, reactivity and toxic effects of RGT. All metabolites are kinetically labile as indicated by LUMO-HOMO energy difference. The molecular modelling analysis shows that M4 and M10 metabolites are readily excreted in urine as their calculated solvation energy is highest.Further, it is found that M1 metabolite might be responsible for edema as it contains acidic group which can form salt bridge with Arg 120 of COX-1.All the metabolites are more reactive than RGT towards nucleophilic attack as indicated by lowest electron affinity of RGT. M13 has the highest HOMO (lowest ionization potential) energy so it will be most susceptible towards electrophilic attack. M1 possesses highest ionization potential in both gaseous as well as aqueous phase.

Author(s): Ashwani Kumar, Sahil Kumara, Sandeep Jaina, Parvin Kumar

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