fragment-based dryg design, biophysical screening methods

Fragment Screening and Fragment Based Drug Design

OVERVIEW

Fragment based approaches in drug discovery (FBDD) have gained high popularity in drug discovery and development processes as alternatives to traditional high throughput screening methods. SARomics Biostructures technology platform offers several biophysical methods for fragment screening, hit identification and structure-based drug discovery (SBDD). In addition, our unique and proprietary weak affinity chromatography (WAC™) technology provides a robust, accurate and high throughput (2000-3000 cmpds/week) way for fragment library screening.

Weak affinity chromatography technology
The WAC™
method is based on covalent immobilization of a protein to be screened on a standard high-performance liquid chromatograph (HPLC) column. The solution of small molecular weight fragments is subsequently injected into the column. During elution, the fragments that have higher affinity for the protein will stay on the column longer than those with low or no affinity. The fragments can be conveniently detected using mass or UV spectrometry. This method is an efficient and lower-cost choice, compared to other methods that study ligand binding, e.g., X-ray crystallography, NMR spectroscopy or isothermal titration calorimetry (ITC). After the initial hit identification, NMR spectroscopy and X-ray crystallography may be used to gain additional insights into the details of the interactions of the fragments with the protein binding site, the amino acid resides involved in the interactions, types of interactions, etc. These in turn can be used, e.g., in calculation of ligand efficiency or ligand binding energy.

A general discussion of drug discovery strategies is presented on our technology section.

Below are the three WAC™ options offered.

WAC™ pilot
Description

• Limited screen of small library < 50 fragments
• Client supply protein
• Preparation of column with immobilized protein
• Screening in duplicates
• Useful as feasibility step for large WAC™ screen
• Fixed price and fast turnaround

Deliverables
• List of hits sorted after Δt
ret
• Short report with technical details

Download pdf…


Biophysical screening methods

Our experts will provide support in the design of the best hit identification and hit-to-lead design and optimization strategy. Our expertise and capabilities in computational chemistry, NMR spectroscopy and X-ray crystallography, thermal-shift assay (DSF), isothermal titration calorimetry (ITC) and Microscale thermophoresis (MST), are applied to ensure the most optimal and time-efficient process. The hit expansion and subsequent optimization programs are run in close collaboration with our partner Red Glead Discovery.

Please view a summary of the available options in the table below (
scroll down to see the whole list).

FBDD platform with full-range discovery services

WAC™ screening technology

Our proprietary WAC™ (weak affinity chromatography) screening technology allows simultaneous identification of weak binders (mM-μM) in complex mixtures, as well as Kd calculation. Detection by LC-MS.


Other biophysical screening methods

The screening platform also uses a range of biophysical screening methods, which include in silico screening, thermal-shift assay (DSF), isothermal titration calorimetry (ITC), Microscale thermophoresis (MST), NMR spectroscopy and X-ray crystallography. in addition, it also offers high-concentration biochemical screening (HCS).


Fragment library

Proprietary library design for easy hit expansion, specifically ordered sets and client libraries. Please enquire for details.


Structural biology

Highly efficient structural biology platform and extensive experience in the use of structural data in hit expansion and lead optimization


Computational chemistry

Extensive experience in hit expansion, pharmacophore- and shape-based virtual screening, scaffold hopping, QSAR analysis and optimization


Medicinal chemistry

Through our collaboration with Red Glead we offer expertise in lead optimization, biological characterization, medicinal chemistry and ADME

Proprietary fragment library
Our library includes a collection of 1300 fragments (available as neat sample, DMSO and DMSO-d6 solutions).
• Designed to be general purpose, (not target-directed) covering diverse chemical space.
• A focus on low-molecular weight fragments (<220)
• Solubility data (DMSO, water) are available for >80% of the fragments
• Analytical data (LCMS, 1H-NMR) available for all fragments
• Designed to be MedChem friendly (HBDs, HBAs and ring count, ClogP, functional groups, etc)
• >90% commercially available facilitating rapid SAR-generation

Exclusive small libraries is also an option available through our academic MedChem collaborations.