Fragment-based lead discovery (FBLD) is a widely used approach in drug research and development. Nowadays, NMR is a powerful approach for implementing FBLD, and several methodologies have been proposed to screen out fragment compounds against a target of interest by employing 1H-15N heteronuclear single quantum coherence as well as one-dimensional 1H and 19F NMR.
Aiming to find novel scaffolds and chemical space, BOC Sciences has established an NMR and Crystal Fragment Library, and these fragments are well suited for high throughput screening based on NMR or X-ray crystallography technology.
Figure 1. Overview of fragment-based discovery. (Fischer, M.; Hubbard, R. E. 2009)
Library Design
- We use the ‘Rule of Three’ to filter all small compounds in the ZINC database according to the following rules:
- Molecular weight≤300 Da
- Number of rotatable bonds≤5
- ClogP≤3.5
- Nmuber of minimal set of minimal rings is 1-4
- Then, further clustering is performed to cluster the resulting fragments into groups with a Tanimoto similarity of 0.7 as a cut-off
- Subsequently, compounds labeled as cluster centers are selected as representatives of these clusters
- The 1H-NMR spectra of these compounds with high diversity are obtained for water solubility determination and group (compound mixture) generation
- The 1H-NMR spectra of the molecular fragments at different concentrations in the screening buffer are recorded to prepare a standard curve. The actual experimental concentrations of these fragment compounds are closely related to their water solubility and are determined by fitting the normalized integrated data for the compounds to establish a standard curve.
- Finally, compounds with water solubility less than 100 μmol/L in PBS buffer (20 mmol/L NaH2PO4/Na2HPO4, 100 mmol/L NaCl, 2% DMSO, pH 7.4) are excluded from the library
Our Services
To make it easier and better for researchers, BOC Sciences has designed a NMR and Crystal Fragment Library containing multiple compound collections. We have prepared the most convenient services for you:
Fluorine Fragment Library
In order to target fluorine-philic sites in proteins, our scientific staffs have created a library of fluorine fragments by adding fluorine atoms into a wide range of aliphatic/aromatic heterocyclic cores and various side chains. We focus on generating high structural quality of molecules and good performance and interpretation of 19F NMR screening results.
Fluorine Fragment Cocktails
The results of fragment screening are able to be increased through pooling or cocktailing the compounds in the library. CD BioScience performs the identification of the bound fragment after carrying out NMR experiments to determine the best fragment-fit. Our experts can construct a Fluorine Fragment Cocktail Library containing small molecule with a single type of fluorine-containing group.
Brominated Fragment Library
Bromine atom plays an essential role in NMR or crystal-based FFBD since bromine can be uniquely located through abnormal scattering, X-ray crystallography and NMR technique are therefore applied to find the location of the fragment bound to the target protein via the presence of the bromine atom. We establish a high quality Brominated Fragment Library consist of more than 1,500 brominated fragments to investigate the target surface pocket.
Halogen-Enriched Fragments Library
It has been proven that affinity and selectivity of ligands can be increased by directed halogen-sulfur contacts with methionines. As a approach that are complementary to those obtained from classical fragment-based screening, Halogen-Enriched Fragments Library is created for us to explore binding sites for favorable halogen bond interactions and identify unique binding modes.
What We Deliver
- A number of high-quality NMR and Crystal Fragment Libraries different in size and design intention
- Comprehensive support in developing your hit compounds
- All compounds have a minimum purity of 90% assessed by 1H NMR
- Analytical data is available
BOC Sciences provides professional, rapid and high-quality services of NMR and Crystal Fragment Library design at competitive prices for global customers. Personalized and customized services of NMR and Crystal Fragment Library design can satisfy any innovative scientific study demands. Our clients have direct access to our staff and prompt feedback to their inquiries. If you are interested in our services, please contact us immediately!
Reference
- Fischer, M.; Hubbard, R. E. Fragment-based ligand discovery. Molecular Interventions. 2009. 9(1): 22-30.
- Dias, D. M.; Ciulli, A. NMR approaches in structure-based lead discovery: Recent developments and new frontiers for targeting multi-protein complexes. Progress in Biophysics & Molecular Biology. 2014. 116(2-3): 101-112.
