The interactions between ketol-acid reductoisomerase (KARI) and its inhibitors were studied by a series of molecular simulation techniques such as MCCE, Autodock and density functional theory. The calculated results indicated that Mg^2＋ ions at the active site played important roles in determining the ionization states of the residues at the active site, electrostatic properties of the active site and ligand binding. The potential inhibitors are similar in the binding mode of KARI, population of the frontier orbitals and electrostatic potentials. The results also identified the ionizable carboxyl groups as a key structural feature for inhibition of KARI. Based on this conclusion, it was further deduced that the potential inhibitors probably had an ionizable group that could release proton and be negatively charged. The conclusions of present study will provide valuable information for designing further potent KARI inhibitors prior to their synthesis.

Key words: ketol-acid reductoisomerase (KARI), inhibitor, Possion-Boltzmann equation, molecular docking, density functional theory