Abstract | About the presenter | Register

Date

Date: Wednesday 22nd October 2025
Time: 2pm GMT / 3pm CET / 9am ET
Duration: 45 minutes
Format: Webinar

Abstract

In their 2013 papers, Liang et al^1,2 presented a large congeneric series of ligands aimed at exploring two areas of binding within the TYK2 active site: the first explored the hinge region while the second investigated the linker region¹. A set of 16 ligands from the first paper is now commonly used as the TYK2 benchmark dataset to test the predictive abilities of FEP. Here we expand on the norm, showing the power of Free Energy Perturbation (FEP) in predicting unknown ligand binding affinities and importantly, how we would triage the results. As the compounds originate from the same project and share a 4-aminopyridine benzamide core, this presented the opportunity to use the TYK2 system from our own Flare™ FEP benchmark experiment for prospective calculations on additional compounds. In this webinar, we will guide you through an efficient workflow using computational methods that are available within Cresset’s software, Flare to arrive at accurate binding free energies for ‘new’ ligand suggestions with the TYK2 system.

The methods used include:

1. Molecular Dynamics (MD)
2. Water analysis solving the Ornstein-Zernike equation (3D-RISM)
3. Alignment of ligands for FEP (Conformation Hunt & Align)
4. Relative binding free-energy (RBFE) perturbation theory (Flare FEP) in both benchmark (for known ligands) and production (involving ligands with unknown activities) modes.

By presenting the FEP results from both the benchmark results and the blind production study, we will show you that Flare FEP can quickly provide valuable insights in drug discovery projects, such as the TYK2 example we discuss here.

References:

1. Liang J., et al. Lead Optimization of a 4‑Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors, J. Med. Chem. 2013, 56, 4521−4536. http://dx.doi.org/10.1021/jm400266t
2. Liang J., et al. Lead identification of novel and selective TYK2 inhibitors, European Journal of Medicinal Chemistry, 2013, 67, 175 – 187. http://dx.doi.org/10.1016/j.ejmech.2013.03.070

About the Presenter

Lauren Nelson, Solutions Scientist

Dr Lauren Nelson completed her PhD in computational chemistry at Newcastle University. Her scientific research focused on the application of quantum mechanical (QM) and molecular mechanical (MM) methods to Free Energy Perturbation (FEP) calculations. During this time, Lauren worked on projects in collaboration with the Northern Institute of Cancer Research and the University of Edinburgh. At Cresset, Lauren has completed the Postdoctoral programme and is now a Solutions Scientist. In her current role, Lauren creates and delivers training material for Cresset products, continues to work with FEP methods, validating Flare FEP and creating case studies including her work with GPCRs, and develops her knowledge of both the structure and ligand based-methods Cresset offers.

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Contact

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