Accurate Calculation of Relative Binding Free Energies between Ligands with Different Net Charges

• DOI: 10.1021/acs.jctc.8b00825
• Publication Date: 2018-10-30T15:01:09Z
• Authors: Wei Chen; Yuqing Deng; Ellery Russell; Yujie Wu; Robert Abel; Lingle Wang
• Keywords: Net (polyhedron)

In drug discovery programs, modifications that change the net charge of ligands are often considered to improve binding potency and solubility, or address other ADME/Tox problems. Accurate calculation free-energy changes associated with charge-changing perturbations remains a great challenge central importance in computational discovery. The finite size effects periodic boundary condition lattice summation employed common molecular dynamics simulations introduce artifacts electrostatic potential energy calculations, which need be carefully handled for accurate calculations between systems different charges. salts buffer solution experimental affinity assays also have strong effect on free energies charged species, further complicates modeling perturbations. Here, we extend our perturbation (FEP) algorithm, has been extensively applied many programs relative same (charge-conserving perturbation), enable We investigated three approaches correct tested them 10 protein targets 31 found all methods able successfully eliminate box-size dependence calculated brute force FEP. Moreover, inclusion matching ionic strength significantly improves energies. For multiple possible protonation states, pKa correction account ionization equilibrium results improved. Finally, from these agree each other, well results. root-mean-square error data is 1.1 kcal/mol, par accuracy charge-conserving anticipate outstanding demonstrated here across broad range target classes may significant implications projects, where must considered.