Harnessing the latest biophysics technology in structure-based drug discovery

The pharma industry’s search for new medicines is complex, with the journey of a drug from lab to shelf taking a considerable amount of time and resources, which can be further delayed by technological limitations.

For example, membrane proteins are notoriously difficult to express and purify for reliable and effective small molecule drug studies, yet an advance in existing technology or a brand-new development can bring those challenging targets within reach and feasible for study. For Swiss drug discovery company leadXpro, it is all about choosing the right technology provider working at the cutting edge of science to deliver advances in the understanding of drug interaction. In this SelectScience interview, we speak with Michael Hennig, structural biologist and CEO at leadXpro, to hear how they teamed up with Creoptix to bring in their interferometry technology and accelerate drug binding affinity and kinetic studies with challenging membrane proteins.

New approaches: Difficult drug targets

Hennig describes how his team’s mission is to create novel small molecule medicines to target the most challenging of diseases such as oncology and the central nervous system (CNS) tackling most challenging membrane protein targets, including ion channels, transporters, and G-protein coupled receptors (GPCRs). “We take the target sequence, express and purify the protein, and then characterize the interaction with small molecules using biophysical, as well as structural methods,” Hennig says.

Those methods can be challenging to apply and, as Hennig explains, some of the most valuable drug targets are not currently used as medicines. “Our mission is to enable the possibility of doing structure-based discovery on such complex targets,” he says. “We have collected a number of key technologies to make this happen, starting with the knowledge and science of construct design, application of different technologies to do the expression of the proteins well, and then to purify functional proteins to “crystal grade quality”.”

However, it is what comes next that has led to Hennig’s fruitful collaboration with Creoptix, as he explains, “we have applied Creoptix’s grating-coupled interferometry (GCI) technology to investigate the affinity of binding and the kinetics of binding of the compounds to the drug target.”

It is the route to this information where the Creoptix™ WAVEsystem has been transformational for leadXpro.

A short video demonstration to show the Creoptix WAVEsystem in action

Selecting the right technology

Hennig describes the Creoptix™ WAVEsystem as a key technology for biophysical measurements of membrane proteins. He explains how his collaboration with Creoptix has been extremely valuable to the success of his business, “we were encouraged by the great sensitivity of the instrument, since the challenges of working with membrane proteins was a key differentiator for us to work with Creoptix and to buy their instrument early, more or less at the time it came to the market.”

As is often the case with winning collaborations, it is also not one-way traffic. Hennig is keen to emphasize how good it has been for Creoptix to have an industry partner showcasing their technology, “the feedback leadXpro is providing to Creoptix helps them to drive new developments in the instrument’s software and hardware,” he explains.

The Creoptix™ WAVEsystem is based around sensitive GCI technology that harnesses no-clog microfluidics, both features of vital importance to the study of membrane proteins and their drug candidates that often face non-perfect properties at the early phase of drug discovery.

Innovative microfluidics and sensitive GCI technology

Hennig outlines the complex challenges of working with membrane proteins and small molecule drug candidates, “we frequently face the challenge that these ligands are pretty hydrophobic and so they tend to stick to surfaces. This is very challenging for microfluidics systems as clogging of the system appears frequently.”

The solution provided by the Creoptix™ WAVEsystem is simple but effective. “Creoptix has invented a really great combination, such that on the chip you have the microfluidics integrated,” Hennig explains. “Consequently, if you have a compound that is sticking to the surfaces or is even blocking the microfluidics, you can bypass all this by just using a new chip that suits the sample size and type, and then continue with your measurements,” he says. Creoptix provides a wide range of disposable chips, which utilize different surface chemistry and can accommodate a variety of sample types and sizes.

The high sensitivity of Creoptix’s GCI technology is also of vital importance to working with membrane proteins. Compared with soluble proteins, such as kinases and proteases, which can be immobilized to high density on the chip surface, membrane proteins achieve limited density of active protein and are often larger in size. With traditional technologies, detecting a good signal to noise ration from those proteins interacting with small molecules is therefore a real challenge. With Creoptix’s high sensitivity GCI, as Hennig explains, “We are able to perform good quality of the measurements enabling detection and analysis of the binding signal.”

Looking ahead

Hennig concludes with a reflection on where leadXpro is heading, “We strongly believe that the leadXpro membrane protein science platform facilitates the design of novel, great medicines, focusing on challenging disease mechanisms,” he says. Hennig and his team expect to make a major impact by using novel, innovative biophysical and structural methods.

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