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MagHelix™ Fragment-Based Drug Discovery (FBDD)

Fragment-Based Drug Discovery or Fragment Based Drug Design (FBDD) has developed rapidly as a new approach in pharmaceutical industry to reduce attrition and identify leads for previously intractable biological targets. Creative Biostructure can perform MagHelix™ fragment library design, fragment screening and elaboration for Fragment Based Drug Design. 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, mass spectrometry (MS), surface plasmon resonance (SPR), virtual screening, etc.

MagHelix? Fragment-Based Drug Discovery (FBDD)

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. Fragment Based Drug Design is an increasing used method in the pharmaceutical industry and emerged as an alternative to HTS. In Fragment Based Drug Design, 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 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.

Fragment Based Drug Design identifies small molecules binding to a protein target, and is compared with high- throughput screening (HTS) as shown in below table:

 

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

References:
Sheldon Park, et al. Targeted inhibitor design: lessons from small molecule drug design, directed evolution, and vaccine research. ChemEng Process Tech 1:1004.
christopher W, et al. The rise of fragment-based drug discovery. Nat Chem. 2009 Jun;1(3):187-92.