XFree Energy Perturbation

Free Energy Perturbation (FEP) is a highly accurate approach to predict the binding strength of small molecule drug candidates to a target protein. FEP allows computing ligand binding free energies by constructing a series of non-physical intermediate states connecting the bound and unbound states. Similarly, FEP allows computing also relative binding free energies between different ligands.

XFEP is XtalPi’s implementation of the FEP method that can accurately compute binding affinities of small-molecule drug candidates at an industrial scale. XFEP enables users to rapidly filter out false-positive molecules, helps scientists make well-informed synthesis decisions with stronger confidence, reduces the number of iterations needed, and thereby enhances the overall success rate of drug discovery projects.

Advantages of XFEP


The XFEP application is based on enhanced sampling algorithms, rigorous data analysis modules, and an advanced force field (XForce Field) developed by XtalPi. XFEP can accurately predict binding affinities of small molecules for a target of interest and effectively reduce the number of false positives.

Thoroughly Tested

As confirmed by both retrospective and prospective testing results, the average prediction error (mean unsigned error) of XFEP in R-group replacement and scaffold-hopping calculations is lower than 1.0 kcal/mol. The predicted values are significantly correlated with experimental data.


Powered by XtalPi's ID4 platform and cloud-based GPU acceleration, XFEP can perform calculations for hundreds of drug candidate compounds within one single day. We are dedicated to developing a fully-automated workflow and easy-to-use interface, which can better serve the optimization of lead compounds as well as lead generation.