# IMERGE-FEP: Improving Relative Free Energy Calculation Convergence with Chemical Intermediates

## TL;DR

This paper introduces IMERGE-FEP, a tool that improves drug discovery simulations by generating intermediate molecules to enhance calculation accuracy.

## Contribution

The novel contribution is the automatic generation of chemical intermediates to improve convergence in free energy calculations.

## Key findings

- Intermediate molecules increase similarity in shared substructures and geometry.
- LOMAP scores improve with the use of generated intermediates.
- The tool simplifies integration of intermediate steps into free energy protocols.

## Abstract

Alchemical free energy
calculations are becoming an increasingly
prevalent tool in drug discovery efforts. Over the past decade, significant
progress has been made in automating various aspects of this technique.
However, one aspect hampering wider application is the construction
of perturbation networks to connect ligands of interest. More specifically,
ligand pairs with large dissimilarities should be avoided since they
can lower convergence and decrease accuracy. Here, we propose a technique
for automatic generation of intermediate molecules to break up problematic
edges—calculations connecting two different ligands or molecules—into
smaller perturbations. To this end, a modular tool was developed that
generates intermediates for a molecule pair by enumerating R-group
combinations called IMERGE-FEP (Intermediate MolEculaR GEnerator for
Free Energy Perturbation). Intermediate enumeration of multiple, representative
congeneric series showed that intermediates increase similarity regarding
shared substructures, geometry, and LOMAP scores. Taken together,
this tool eases integration of intermediate steps into free energy
calculation protocols.