FEP calculation results typically fall within 1kcal/ mol from experimental data enabling accurately informed decisions on which ligand modifications can achieve the best results, with new molecule designs often significantly different from the initial molecular structure and with enhanced potency. Free energy perturbation software supports scientists in making known actives more potent, without having to synthesize hundreds or thousands of compounds, eliminating the time wasted on synthesizing non-potent molecules.
Lead optimization or hit to lead?
Whether you’re refining a promising hit or comparing multiple candidates, relative and absolute FEP offer powerful insights at different stages of drug discovery:
Relative FEP
Relative Binding Free Energy (RBFE) Perturbation calculates the relative free energy of binding between two ligands and the target
- Best for lead optimization: Quickly compare small modifications in a chemical series
- Highly efficient: Requires shorter simulations, making it fast and cost-effective
- Great for ranking analogs: Determine which modifications improve binding affinity
- Excellent for fine-tuning: Make data-driven decisions on subtle molecular changes
Absolute FEP
Absolute Binding Free Energy (ABFE) Perturbation calculates the binding strength of a ligand into a protein target
- Best for hit-to-lead: Accurately predict binding affinities of new chemotypes
- Essential for early-stage drug discovery: Identify promising starting points with confidence
- Absolute binding free energy predictions: Directly assess compound-target interactions without the need of a congeneric ligand series
Stages of an FEP Project
There are two phases of an FEP project. Benchmarking FEP experiments can be used to gain confidence that your system is prepared correctly, confirming the predictivity of the method on the target and ligand series of interest. Then production FEP experiments yield predicted binding free energies for new molecular designs.
Benchmark
The validation process also known as ‘benchmark’ mode, uses known active molecules in their defined binding mode to assess the stability of the protein-ligand complex and the accuracy of the FEP calculation using the specific target and ligand binding mode. This phase is a critical factor for a successful FEP calculation as it allows for early identification of problematic regions of the molecular systems and localized redevelopment of the protein-ligand model to improve the calculation in these regions.
Production
Once the required level of accuracy is reached in the set of compounds used in the validation phase, the production phase can begin. New compounds with unknown activities are imported, and additional FEP calculations are deployed to predict their activity and hence rank them for synthesis or purchase.
What are the data requirements to run an FEP project?
The three ideal data requirements for an effective FEP project can be summarised as:
The availability of a high-quality crystal structure with a relevant ligand – a crystal structure to a resolution below 2.2 Å is ideal
The quantity and quality of a dataset of ligands for validating the experiment set up and model
The generation of an appropriate ligand set for prediction
Flare™ FEP: robust and accurate prediction of binding affinity
- In silico testing of ligand binding affinity
- Cost-effective free energy calculations to accelerate your discoveries
- Reduce time and cost of drug discovery projects
- Prioritize compounds for synthesis
- Spend less time on wet chemistry
- Make informed decisions on ligand modifications
- Enable lead optimization with confidence
Advancing free energy perturbation predictions
Flare™ FEP has been in continuous development since 2019 and with each release users benefit from the latest validated methods. Flare is used on drug discovery programs in both industry and academia.
Flare FEP’s innovative features and workflows can be used from the beginning to the end of your project to streamline your FEP calculations and includes tools for preparing the molecular system of interest, run and troubleshoot the FEP calculation, analyze the results and decide the next steps. Learn more about setting up and running an FEP experiment in Flare FEP.
Expertise to advance your FEP project
Even if you don’t have in-house FEP expertise, the Cresset Discovery CRO’s experienced team has an extensive and growing portfolio of successfully completed FEP projects.
With their deep knowledge and expertise of the theory and method implementation, combined in synergy with Cresset’s cutting-edge solutions, the team can support or completely manage your FEP project.
Learn more about outsourcing an FEP project to Cresset Discovery and contact us for a confidential discussion about your goals. We can advise on whether FEP would be suitable for your project, and identify the best approach to accelerate your project.
Ready to accelerate drug discovery with FEP?
Contact us today for a fully-supported evaluation and quickly get started in assessing if FEP is right for your project. Our dedicated team are on hand to support you during every step.
We’re here to help you reach your goals, faster, enabling you to make the molecules that matter.
Download our white paper
Want to learn more about FEP? Download our whitepaper below to learn more about accelerating drug discovery using free energy perturbation (FEP) calculations in this whitepaper from Cresset with C&EN.
