David Myszka, founder of Biosensor Tools LLC and director of the Center for Biomolecular Interaction Analysis at the University of Utah, used surface plasmon resonance (SPR) to screen small molecules (fragments) in the Maybridge Ro3 collection against stabilised G-Protein Coupled Receptors (GPCRs) provided by Heptares Therapeutics1. Several new classes of compounds were identified from the Ro3 library, which is accelerating drug discovery efforts around these receptors
Dr Myszka’s study demonstrated for the first time that fragment screening by SPR is an effective approach. It utilises the sensor surface to purify and concentrate solubilised tagged GPCRs and then characterise their binding activities with the fragments.
Dr Myszka and Rebecca Rich, a research scientist in Dr Myszka’s group, recently presented their work, "Fragment Screening against Membrane Receptors using SPR,” at the Fragment-Based Lead Discovery Conference in Philadelphia and at the Developments in Protein Interaction Analysis symposium in Barcelona, Spain.
“While fragment screening by SPR has become standard practice, this is the first example of a successful SPR-based fragment screen against GPCRs,” said Dr Myszka. “One major factor contributing to our success was the integrity of the Maybridge Ro3 Fragments. The library was well-behaved in terms of high solubility and displayed minimal nonspecific binding or so-called promiscuous binders. In addition, the structural diversity within this library allowed us to span a lot of chemical space, helping us to identify subsets of novel compounds that targeted two GPCRs. From the primary screen we identified thematic structural elements in the hits and then selected analogs from within the full Maybridge collection to investigate as confirmatory hits. With these follow-up studies in hand, we are now poised to pursue the next stage in elaborating compounds for drug development.”
“The guaranteed aqueous solubility of Maybridge Ro3 Fragments is not only key from a practical perspective, but it also provides an insight into likely ADME problems as the hits are evolved into drug-like molecules,” said Simon Pearce, product manager for Maybridge products at Thermo Fisher Scientific. “Furthermore, pharmacophoric enrichment and quality assurance of at least 95 percent, with full Rule of Three (Ro3) compliance, meant that all fragments used for the study possessed physicochemical properties that also increased the probability of successful hits.”
Thermo Fisher Scientific and Dr Myszka are continuing their collaboration as the study now expands to drug development using additional Maybridge Ro3 Fragments.
The Maybridge Ro3 Diversity Fragment Library is a carefully engineered set of structurally diverse fragments, recently expanded to 1500 products. All Fragments hold an experimental guarantee of solubility (aqueous >=1mM / DMSO >= 200mM) to provide a robust and rich source of optimizable hits for screening programmes. The library is available pre-plated in 500 compound sets for varied level entry points into fragment based drug discovery. Each set has been selected to offer the same pharmacophysical and diversity profile as the complete 1,500 library. For more information about Maybridge products, please also visit www.maybridge.com.
Reference :
1. Robertson, N., et al. The properties of thermostabilised G protein-coupled receptors (StaRs) and their use in drug discovery. Neuropharmacology 60, 36-44 (2011).
Thermo Fisher Scientific
