Fragment-Based Drug Discovery (FBDD) has developed rapidly as a new approach in pharmaceutical industry to reduce attrition and identify leads for previously intractable biological targets. Creative Biostructure performs MagHelix™ fragment library design, fragment screening and elaboration for FBDD. We also provide various screening methods to determine the exact binding fragment(s), which include fluorescence-based thermal shift (TS), NMR spectroscopy, X-ray crystallography, electron microscopy (EM), surface plasmon resonance (SPR), virtual screening, etc.
In order to find small-molecule drugs, it is a key step to identify some new chemical leads. Up to now, there are mainly four approaches used to obtain chemical leads. Firstly, one of the dominant methods is high-throughput screening (HTS). HTS enables testing a larger number of diverse chemical substances against targets. After a few millions of compounds are screened, identified ones are followed up and optimized into leads. The characteristics of HTS include simplicity, rapidness, low cost, high efficiency, etc. FBDD is an increasing used method in the pharmaceutical industry and emerged as an alternative to HIS. In FBDD, various techniques are used in library screening. Usually, the library is consisted of fragments between 150-250kD (<300kD). The fragments are a diverse set of chemical scaffolds and functionalities which are usually well precedent in drugs. And the binding mode is established in the protein target of interest. Due to the small size of fragments, they often have low potency but they can form high-quality interactions and can be optimized into potent leads by linkage (shown in the above figure). The detailed comparison between HTS and FBDD is shown in the following table. Besides HTS and FBDD, the new chemical leads can also be from existing leads or drugs or from natural products. For the two methods, which are old but very successful, it is important to identify new compounds with biological/clinical advantages and good intellectual property position relative to the original compound. All these strategies have their effects in drug discovery. Recently FBDD has caused a revolution and many FBDD leads have been processed into clinical trials. FBDD can be extended to more researches and a broader range of applications.
FBDD identifies small molecules binding to a protein target, and is compared with high- throughput screening (HTS) as shown in below table:
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FBDD | HTS |
| Library Capacity | Library typically <5,000 | Library typically >100,000 |
| Molecular Weight | Molecular weight <300Da | Molecular weight >300Da |
| Affinity | Affinities typically in the mM range | Affinities typically in the μM range |
| Coverage | A much greater chemical space can be efficiently probed | Coverage of chemical space can be poor |
| Target Specificity | Well characterized targets | Broader range of targets including whole-well screening approaches |
| Ability | Iterative step-by-step optimization possible to increase the size and potency of the molecule | Can be difficult to optimize hits as the structures can be complex |
| Throughput | Low-medium throughput | High throughput |
Creative Biostructure provides full range of services for drug discovery and drug design. Please feel free to contact us for a detailed quote.
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