A comparative study of binding affinities for 6,7-dimethoxy-4-pyrrolidylquinazolines as phosphodiesterase 10A inhibitors using the linear interaction energy method

作者：Kjellgren Erik Rosendahl; Glue Oliver Emil Skytte; Reinholdt Peter; Meyer Julie Egeskov; Kongsted Jacob; Poongavanam Vasanthanathan^*

来源：Journal of Molecular Graphics and Modelling, 2015, 61: 44-52.

DOI：10.1016/j.jmgm.2015.06.010

• Phosphodiesterase 10A
• Schizophrenia
• Pyrrolidylquinazoline
• Binding affinity
• Linear interaction energy
• Virtual screening and applicability domain

The linear interaction energy (LIE) method was used to estimate the free energies of binding for a set of 27 pyrrolidylquinazoline derivatives as phosphodiesterase 10A inhibitors. Twenty-six X-ray crystal structures of phosphodiesterase 10A and two sampling methods, minimization and Hybrid Monte Carlo, were used to assess the affinity models based on the linear interaction energies. The best model was obtained based on the parameters alpha = 0.16 and beta = 0.04, which represent non-polar and polar interactions, respectively, with a root mean square error (RMSE) of 0.42 kcal/mol (R-2 = 0.71) and 0.52 kcal/mol (R-2 = 0.86) for the training and test sets, respectively. In addition, the applicability domain of the model was investigated. After validation of the models, the best model was subsequently used in a virtual screening process, which resulted in a set of optimized compounds. The models developed in this study could be useful as filter for virtual screening and lead optimization processes for phosphodiesterase 10A drug developments.

• 出版日期2015-9