Red Glead Discovery (RGD) in partnership with SARomics Biostructures operates an integrated fragment-based lead discovery platform enabling hit finding and validation for a wide variety of biological targets. We offer strong experience creating high quality starting points for hit-to-lead Medicinal Chemistry programs designed to efficiently drive the project to the next milestone.
Why choose us
There are many advantages in using libraries of a few hundred up to thousands of fragments (small molecules of a molecular weight of 120 – 300 g/mol) instead of vast libraries of larger substances. Besides significant savings in cost and time, the fragment-based lead discovery (FBLD) approach has repeatedly demonstrated its high potential in generating innovative and novel chemical entities for fast progression into clinical trials. With a range of versatile and diverse fragment screening technologies, RGD can customise a fragment screen campaign according to various drug targets and the needs of clients and partners. If the drug target is feasible for immobilization on a LC column, we exclusively offer weak affinity chromatography (WAC™) as a cost-efficient, high-throughput method for the initial step in the fragment screening process. WAC™ can be used as a stand-alone technique as well as in combination with other complementary techniques. The exact strategy is always carefully tailored to the needs and budget of each client project.
Fragment Screening & Integrated drug discovery
Our FBLD Team collaborates closely with the Biology, Computational Chemistry and Medicinal Chemistry Teams affording a fully integrated solution designed to efficiently drive the project from target validation through hit finding and expansion, to lead optimisation and ultimately – candidate drug nomination.
A pharma company set out to screen their internal library of 10 000 compounds against a protein target with the aim to find new site-selective chemical starting points. A screen was designed where wild-type and mutant versions of the protein were immobilized on a WAC column. The library was then passed though both columns, revealing hits only active towards the site of interest found on the WT version of the protein.
A biotech company identified a promising target and demonstrated its implication in oncological conditions through a novel mechanism. It was important to confirm if it could be a target for a drug discovery program, so a ligandability fragment screen by WAC was planned and executed. This screen revealed that the target was amenable for drug discovery. Based on this finding a detailed drug discovery plan was proposed aiming to take the program to in vivo proof of concept stage.
WAC™ – weak affinity chromatography (proprietary technology)
NMR – primarily ligand-detected 1D 1H/19F NMR techniques
DSF – differential scanning fluorimetry (i.e. thermal shift assay)
HCS – high concentration screening using functional readout, e.g. biochemical assay
CFS – crystallographic fragment screening
As a follow-up activity to confirm found hits in the primary screening and remove false positives, we apply a secondary method with orthogonal output, normally NMR, DSF and/or X-ray crystallography. LC-MS and NMR are also used to confirm the purity and identity of the obtained active fragments.
Evaluation and prioritisation of active fragments can be performed by the client or by our team of medicinal and computational chemists with supporting data obtained from our in vitro biology and ADME capabilities.
WAC™ – weak affinity chromatography (proprietary technology) is a powerful technique for primary screening of fragment libraries and is an integral part of our FBLD platform. This unique technology originates from the academic research of Professor Sten Ohlson and his co-workers. The commercial rights of WAC are fully owned by RGD and SARomics Biostructures AB. Principles and advantages of WAC™:
- Physiological buffer as mobile phase
- Target protein immobilized on HPLC column
- Detection by LC-MS
- Simple detection of retention times
- Kd calculated from retention time
- Allows simultaneous identification of weak binders (mM) in complex mixtures
- High throughput potential (up to 3000-4000 fragments per week)
- Finding mM hits by screening at 1-5 µM
- Hit ranking / Quality control