In drug discovery programs, modifications that change the net charges of ligands are often considered to improve binding potency, to enhance solubility, or to address other ADME/Tox problems. Accurate calculation of the binding free energy changes associated with charge-change perturbations remains a great challenge of central importance in computational drug discovery. The finite size effects associated with periodic boundary condition and lattice sum employed in common molecular dynamics simulations introduce artifacts in electrostatic potential energy calculations, and these effects need to be carefully handled for accurate free energy calculations between systems with different net charges. Here, we extend our free energy perturbation algorithm, which has been extensively applied to many drug discovery programs for relative binding free energy calculations between ligands with the same net charge (charge-conserving perturbations), to enable charge-change perturbations. We investigated three different approaches to correct finite size effects and tested them on ten protein targets and thirty-one charge-change perturbations. We found that the calculated binding free energies from these methods agree with each other, and also agree well with experimental results. The root-mean-square error between the calculated binding free energies and experimental data is 1.1 kcal/mol, comparable to that of charge-conserving perturbations. We anticipate the outstanding accuracy demonstrated here across a broad range of target classes may have significant implications for drug discovery projects where modifications changing the net charges of ligands need to be considered.

Accurate calculation of relative binding free energies between ligands with different net charges

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.