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Free Energy Perturbation Calculations on Glucosidase-Inhibitor Complexes

[ Vol. 1 , Issue. 5 ]


F. M. Ruiz and J. R. Grigera   Pages 455 - 460 ( 6 )


Free energy perturbation studies have been performed on Glucoamylase II (471) from Aspergillus awamori var. X100 complexed with three different inhibitors: (+)lentiginosine, (+)(1S,2S,7R,8aS) 1,2,7-trihydroxyindolizidine, (+)(1S,2S,7S,8aS) 1,2,7-trihydroxyindolizidine and the inactive compound (+)(1S,7R,8aS)-1,7-dihydroxyindolizidine. Molecular dynamic simulations were carried out using a recently developed procedure for fast Free Energy Perturbation calculations. In this procedure only a sphere of 1.8 nm around the central atom of the inhibitor is considered in the calculations. Crystallographic restraints are applied over this reduced system using a generated electron density map. The obtained values for the free energy differences agree with experimental data showing the importance of fast calculations in drug design even when the crystallographic structure of the complex is not available. As the method uses only the crystallographic structure of the receptor, it is possible to test the possible efficiency of even still not synthesised ligands, making the pre-selection of compounds much easy and faster.


glycosidase inhibitors, free energy calculation, glycosidase complexes


Instituto de Fisica de Liquidos y Sistemas Biologicos - IFLYSIB (UNLP - CONICET-CIC) andDepartamento de Ciencias Biologicas, Fac. de Ciencias Exactas Universidad Nacional de La Plata, c.c. 565, B1900BTE, La Plata, Argentina.

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