Adequate prediction for inhibitor affinity of A(40) protofibril using the linear interaction energy method

摘要

The search for efficient inhibitors targeting A oligomers and fibrils is an important issue in Alzheimer's disease treatment. As a consequence, an accurate and computationally cheap approach to estimate the binding affinity for many ligands interacting with A peptides is very important. Here, the calculated binding free energies of 30 ligands interacting with 12A(11-40) peptides using the linear interaction energy (LIE) approach are found to be in good correlation with experimental data (R = 0.79). The binding affinities of these complexes are also calculated by using free energy perturbation (FEP) and molecular mechanic/Poisson-Boltzmann surface area (MM/PBSA) methods. The time-consuming FEP method provides results with similar correlation (R = 0.72), whereas MM/PBSA calculations show very low correlation with experimental data (R = 0.27). In all complexes, van der Waals interactions contribute much more than electrostatic interactions. The LIE model, which is much less time-consuming than both the FEP and MM/PBSA methods, opens the door to accurate and rapid affinity prediction of ligands with A peptides and the design of new ligands.