PairMap: An Intermediate Insertion Approach for Improving the Accuracy of Relative Free Energy Perturbation Calculations for Distant Compound Transformations.

ABSTRACT: Accurate prediction of the difference in binding free energy between compounds is crucial for reducing the high costs associated with drug discovery. Relative binding free energy perturbation (RBFEP) calculations are effective for small structural changes; however, large topological changes pose significant challenges for calculations, leading to high errors and difficulties in convergence. To address such issues, we propose a new approach─PairMap─that focuses on introducing appropriate intermediates for complex transformations between two input compounds. PairMap-generated intermediates exhaustively, determined the optimal conversion paths, and introduced thermodynamic cycles into the perturbation map to improve accuracy and reduce computational cost. PairMap succeeded in introducing appr

SUBMITTER: Furui K 

PROVIDER: S-EPMC11776053 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature