Accurate and rapid evaluation of relative change in binding affinity (ΔΔG) associated with a given structural modification to a ligand is an important requirement for computational methods to facilitate and lead the drug-design process. Among the different approaches available, free energy perturbation (FEP) methods are widely adopted due to their overall accuracy. However, they require significant computational resources for each planned modification. Single-step free energy perturbation (SSFEP) is an attractive alternative that is based on repeatedly reusing a pre-computed ensemble of conformations of a parent ligand in explicit solvent and solvated protein environments. This allows for the rapid evaluation of ΔΔGs for a library of small functional group substitutions. Instead of a gradual alchemical transition through non-physical states, SSFEP utilizes the perturbation formulation to evaluate ΔΔG through a single-step transformation between the parent and the modified ligand. Consequently, SSFEP is on the order of one thousand times faster than traditional FEP methods. While originally SSFEP was designed for a single heavy atom substitution, to expand the functional group library that can be evaluated, we report a new protocol where rotatable dihedrals along a modification are explicitly sampled during the transformation. This development allows for evaluating functional group substitutions up to four heavy atoms and three rotatable dihedrals. For ligands targeting three different proteins: Ack1, p38 MAP Kinase and Farnesoid X receptor (FXR), SSFEP’s prediction of the directionality of ΔΔG across a defined set of modifications to the parent ligand was found to be competitive with FEP. 5/8, 9/15 and 12/15 modifications to ligands targeting Ack1, p38 MAP Kinase and FXR, respectively, were correctly identified using SSFEP, whereas FEP methods identified 4/8 and 10/15 modifications to ligands targeting Ack1 and p38 MAP Kinase correctly. These results show that SSFEP holds potential as a new computationally tractable strategy that can lead the drug-design process.

Rapid evaluation of relative change in binding affinity using single step free energy perturbation (SSFEP)

254th National Meeting (2017)

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