ΔG ‡ prediction of PME-1 inhibition using information science

Abstract

Recently, computational chemistry as well as chemoinformatics plays an important role in theoretical consideration of chemical reactions. In the present study, we tried to predict the activation free energies (ΔG‡) calculated for substrates with different substituents without searching transition states, one of the most difficult problems in computational chemistry. For that purpose, we adopted a reaction of aza-β-lactam which inhibits the activity of protein phosphatase methylesterase 1 (PME-1). A methanol was used for the model of the serine residue of PME-1. The mechanism of the ring opening reaction including a water molecule was analyzed and ΔG‡ values were calculated as the objective variable for PLS regression. Explanatory variables are HOMO and LUMO energy levels of the reactants, the parameters related to the structure factor from the GRAGON program, and molecular volumes using the Winmoster program. The Chemish program gave a good regression model with R2 = 0.932 and Q2 = 0.915. The major part of the model consisted of LUMO energy and Hammett's σ value.