Flare FEP

Flare™ FEP, developed by Cresset, is a powerful computational tool designed to reliably calculate absolute and relative binding affinities for small molecules in drug discovery. By leveraging Free Energy Perturbation (FEP) methodology, it enables medicinal chemists and computational scientists — from novice to experienced users — to make smarter, more confident ligand design decisions throughout lead discovery and optimization campaigns.

Flare FEP reduces the reliance on extensive wet lab experimentation by providing accurate in silico binding affinity predictions, offering a cost-effective and time-saving approach to identifying and progressing the most promising drug candidates. Its intuitive interface ensures that advanced computational capabilities are accessible to a broad range of users across all stages of drug discovery.

Key Capabilities

• Accurate calculation of both absolute and relative binding affinities for molecules against therapeutic targets
• Prioritization of compounds for synthesis, focusing resources only on the most promising molecules
• Reduction of wet chemistry requirements across all stages of the drug discovery pipeline
• Increased efficiency in designing new compounds for key therapeutic targets
• Identification of drug candidates with enhanced potency at the target of interest
• Effective triaging and prioritization of the most promising candidates for further investigation

Integration and Workflow

• Seamless integration with other Flare methods, including 3D pose generation, Water analysis, and Molecular Dynamics, for a comprehensive approach to binding affinity prediction
• Integration with complementary Cresset software solutions and modules such as Hit Expander and Spark™ to support end-to-end ligand design workflows
• Support for perturbations involving ligands with different charge states within the same calculation, enabling broader applicability across chemical series
• Active learning workflows using FEP combined with 3D-QSAR to efficiently identify the strongest-binding bioisosteric replacements
• Applicability to macrocyclic design prioritization, helping address the synthetic challenges associated with macrocyclic compounds

Scientific Validation and Resources

• Published case studies and citations demonstrating FEP applications, including TYK2 ligand binding affinity prediction and Cyclophilin B-targeted inhibitor optimization for MASH treatments
• Validation of AI protein structure prediction models using Flare FEP calculations, supporting integration of AI-generated structures into binding free energy workflows
• Benchmarking studies on alchemical binding free energy calculation methodologies, including modular and interoperable workflow assessments
• Whitepapers and webinars covering topics such as accelerating small-molecule drug discovery with FEP and empowering medicinal chemists with AI

Flare FEP is part of the broader Flare platform from Cresset, which in its latest V11 release incorporates generative AI tools, constrained Protein-Protein Docking, detached calculations, and numerous enhanced features — positioning it as a continually evolving solution for modern computational drug discovery.