Assessment of Computational Methods for Ligand Binding

Sammanfattning: Most drugs act on biomacromolecules. The Cost of developing new drugs is very high. A method to accurately predict binding affinities would be very useful. We have studied molecular mechanics with generalised Born and surface--area solvation (MM/GBSA) and alchemical free energy perturbation methods (FEP) for use in calculations of ligand binding energies. For the MM/GBSA method we have tested: Calculating the non-polar solvation term with the polarized continuum model, a method based on cavity and dispersion terms, and a method based on a linear relation to the solvent-accessible surface area. Replacing molecular mechanics terms with energies calculated with the semiempirical quantum mechanics AM1, RM1, PM6 Hamiltonians, and adding hydrogen bond and dispersion corrections. Inclusion of explicit water in the binding site of a protein. Effect of system truncation on estimated energies. The results show that for continuum solvation models knowledge of hydration state of binding site is important. The rest of variations of the MM/GBSA method for the tested systems showed only minor improvements. We have done a large systematic study of calculating relative binding free energies for 10 proteins binding 107 ligands with Bennett acceptance ratio (BAR) method. For the most of systems binding affinities could be calculated within 4 kJ/mol of experimental values. We have also participated in the SAMPL3 and SAMPL4 blind binding challenges to see how the MM/GBSA and FEP methods perform. The MM/GBSA failed to predict experimental binding affinities, which might be due to poor precision of the method as experimental data had very narrow range of about 9 kJ/mol. In SAMPL4, the BAR method gave the best predicted binding affinities.