Abstract

Modeling and characterization the transition state structure of enzyme catalyzed reactions is essential. A DFT method employing B3LYP level of theory with 6-31G (d',p') basis set for non-metals and LanL2DZ basis set for molybdenum have been used. The bond orders of chemical fragments were calculated using AOmix softaware. The effect of chalcogen replacement, amine group and methyl group in the parent structure of xanthine bound to xanthine oxidase active site were compared. The transition state structure of model substrates (2AX, 2A6TP, 2A6SP and 2A6MP) bound to the truncated form of XO active site has been confirmed by the presence of one negative imaginary frequencies (s^-1) (-60), (-140), (-230) and (-270), respectively. The corresponding normalized energy barriers (kcal/mol) from pre-transition state to the transition state, respectively, are (13.869), (21.753), (23.109) and (0.212). In this work, 2A6SP and 2A6TP substrates were found to be potential xanthine oxidase inhibitors. The large bond distances and minimum bond order for C_RH-H_RH bond, and small bond distances and maximum bond order for S_Mo-H_RH bond at the transition state for chalcogen replaced 2AX confirms early transition state structure. Methyl substituted 2AX analog found to have post transition state structure. A potential xanthine oxidase inhibitor can be designed from purine family enzymes using DFT approach.

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