Cresset releases Flare V12 to cut synthesis and testing cycles with faster, more flexible FEP

Cresset has released Flare V12, the latest version of its computer-aided drug design (CADD) platform for the discovery, design and optimization of small molecules in drug discovery programs worldwide.

This new release focuses on making Free Energy Perturbation (FEP) calculations faster, more accessible and more applicable to complex medicinal chemistry, so discovery teams can prioritize which compounds to synthesize and test more confidently and cost-effectively.

Addressing barriers to Free Energy Perturbation in drug discovery

FEP is a physics-based method used to predict how strongly small-molecule drug candidates bind to their biological targets, helping guide compound selection and optimization. Although FEP is recognized for its accuracy, its broader adoption in pharmaceutical and biotech research has been limited by high computational cost, usability challenges and difficulties in modeling complex chemical transformations.

Flare V12 is designed to overcome these barriers by combining a new simulation engine, improved workflows and extended molecular dynamics capabilities. The goal is to make FEP and related methods practical for routine use across discovery projects, not just within specialist simulation teams.

Cutting computational cost to improve throughput

One of the main obstacles to wider use of FEP has been computational expense and long runtimes. Flare V12 introduces a new simulation engine and workflow that reduce calculation times by more than 50% compared with the previous version, while maintaining excellent predictive performance.

For discovery teams, the benefit is the ability to make design decisions faster across entire projects. Small-molecule discovery campaigns typically generate many plausible design ideas but have limited capacity to synthesize and experimentally test them. Faster and accurate FEP calculations increase throughput, enabling teams to evaluate more compounds in silico and focus laboratory resources on the most promising molecules.

Expanding FEP support for complex medicinal chemistry

Flare V12 extends FEP capabilities to better handle complex chemical transformations commonly explored in medicinal chemistry. Ring-breaking transformations enable researchers to model scaffold hopping, cyclizations and ring size modifications in a single step, providing streamlined support for these frequent structural changes.

The Flare FEP implementation in this release also introduces methods to improve predictive accuracy. Replica Exchange is available for broader conformational sampling, while Grand Canonical Monte Carlo is used during the production phase for enhanced water sampling, particularly in buried binding sites where water behavior can strongly influence binding affinity.

Extending molecular dynamics to emerging therapeutic modalities

Beyond FEP, Flare V12 extends molecular dynamics simulations to support covalent ligands, non-standard amino acids and post-translationally modified proteins. These systems are increasingly important in areas such as targeted covalent therapeutics and peptide drug design.

With Flare V12, enhanced parameters for these more complex systems are automatically calculated and seamlessly incorporated into simulations. This helps researchers explore a broader range of therapeutic modalities within a single CADD environment.

Supporting better compound progression decisions

Taken together, the updates in Flare V12 reflect a shift toward making Flare more usable beyond specialist simulation groups and more practical as part of routine drug discovery workflows. Flare is a complete molecule design solution, where FEP can be combined with a wide range of complementary methods to rigorously evaluate and validate high-value design ideas before synthesis.

“The core challenge in discovery is deciding which compounds to make when synthesis is expensive and timelines are tight,” said Tim Cheeseright, CEO of Cresset. “FEP has the potential to bring clarity to those decisions, but historically it has been difficult to apply consistently. With Flare V12, we have focused on making these methods faster, easier to use and applicable to a much broader range of chemistry so teams can prioritize compounds with greater confidence and reduce unnecessary synthesis.”

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