Cresset User Group Meeting 2021

Overview

We welcome users and non-users alike to hear Cresset scientists present our latest science, and showcase upcoming solutions to help your chemists design the best molecules as efficiently as possible. Case studies will be presented by users from Bayer AG and Merck KGaA.

Who should attend by role?

Computational chemist • Medicinal chemist • Synthetic chemist • Flavor chemist • Fragrance chemist • Head of discovery • Head of modeling and simulation • Head of R&D • Research Scientist • CSO

Who should attend by industry?

Pharmaceutical • Agrochemical • Biotech • Flavor • Fragrance • Chemical

Agenda: June 16^th

Connecting ligand-based methods in Flare™

Chaired by: Tim Cheeseright, Director of Products

Agenda: June 17^th

Working at the edge of structure-based design

Chaired by: Tim Cheeseright, Director of Products

Abstracts

Introducing Flare V5, your integrated platform for ligand and structure-based design

Giovanna Tedesco, Head of Products

The seamless integration of Forge™ ligand-based methods has evolved Flare™ into a platform where ligand and structure-based methods work in synergy to inform the design of the next generation of drugs. We will introduce the new science, features and enhancements of ligand-based methods in Flare V5, and present the plans for the future evolution of Flare as an integrated platform for drug discovery.

The science behind ligand-based design in Flare V5

Mark Mackey, CSO

In this talk we present all the new features for ligand-based design in Flare. This includes changes to our field algorithms, access to our advanced conformer generation and ligand alignment algorithms through a new Python API, and more.

BaySpace3D searching large 3D spaces

Jens Schamberger, Bayer; Rosemary Mantell and Hannes Loeffler, Cresset

At present the usefulness of large chemical spaces is limited as no 3D pharmacophore method exists to navigate them without brute force enumeration. With BaySpace3D we developed a high-quality 3D pharmacophore method as a more sophisticated and reliable way to quickly search large combinatorial libraries. The method uses a fragmentation and recombination approach within Cresset’s Spark tool to rapidly locate regions of the library space which are similar to the query molecule in terms of shape and electrostatics. A Bayer proprietary space of about 200 million novel compounds can be searched in around 2 hours. Lead finding and optimization at Bayer will benefit greatly from BaySpace3D as new leads and ideas can be derived from Bayer’s novel and synthetically well described virtual 3D library.

Building meaningful models: Application to cardiac inotropy

Nathan Kidley, Senior Application Scientist

In silico models are used extensively in drug discovery to help predict activity and alert the project team to potential issues. However, models must be both robust and trustworthy to gather confidence and materially affect project outcome. This is especially true with general safety models built on sparse data. We will present how we applied Cresset’s ligand and structure-based approaches to build predictive models against multiple primary and off-target/secondary end points for both positive and negative cardiac inotropy effects. Critical to success was the bootstrapping of any resulting score with a probability that the result was meaningful. The validated in silico models were integrated into a web-based application to enable drug discovery project teams to profile their compounds for potential inotropic side effects.

New and improved structure-based methods in Flare and docking in Spark

Giovanna Tedesco, Head of Products

We will give an overview of the new and improved structure-based methods in Flare and Spark. In Flare, these include a new molecular dynamics-based water analysis with GIST, significant enhancements to FEP speed and accuracy, enhanced molecular dynamics, protein minimization and docking, and many other new features and improvements. The latest version of Spark, our ever-popular bioisostere application, now includes the ability to grow ligands into empty pockets in the protein. During this presentation you will be guided through the new docking feature, which enables you to find results that make new ligand-protein interactions for your molecules.

The science behind structure-based design in Flare V5

Mark Mackey, CSO

In this talk we present the new science in Flare V5. This includes major improvements to our Free Energy Perturbation (FEP) workflow, access to a new water analysis method, and sneak peeks at exciting new research coming out of the Cresset labs.

Benchmarking Flare FEP and Open Force Field at Merck KGaA

Christine Schindler, Merck KGaA

Free energy calculations have become a powerful addition to the computational chemist’s toolbox to support structure-based drug design in hit-to-lead and lead optimization stages of drug discovery projects. Here, we present an evaluation of the accuracy of Flare FEP on a subset of the Merck FEP benchmark and datasets from two in-house projects. We also report results of an evaluation of the Open Force Field on a large set of proprietary molecules with respect to geometry optimizations as well as using this force field in free energy calculations.

The synergistic relationship between ligand and structure-based methods in Flare

Stuart Firth-Clark, Senior Application Scientist

Using all the available ligand and protein information to build reliable molecular models is key to unlocking the power of computational chemistry when developing new ideas for your drug discovery project. We will show how the introduction of ligand-based methods into Flare V5 has enabled a more detailed, informative view of project data. Using real world data, we will demonstrate how using ligand and structure models synergistically, especially in combination with accurate visualization of electrostatics, provide vital insights for ligand design.

Register

Registration for this event has now closed. If you were unable to attend, presentation recordings from this event are available upon request.