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Fragment Based Drug Discovery (FBDD) and Fragment Based Screening (FBS)
Fragment Based Drug Discovery (FBDD) and Fragment Based Screening (FBS)
‘Fragment’ compounds are characterised by their low molecular weight (classically, Mw < 300 Da), resulting in low complexity. Therefore, hit fragments bind to their target with weak affinity compared to ‘small molecule’ hits (Mw < 500 Da). However, the modest molecular size of fragments enhances their ability to access an optimal spatial orientation relative to binding features at the target. This presents a simpler starting point for drug design compared to larger, higher affinity hits, whose greater complexity may hinder the formation of optimally directed interactions towards each molecular recognition element at the target. These fragment hits are then grown or merged or linked with other hits in a process known as fragment optimisation. A second advantage of using fragments to provide a starting point is that the same number of compounds can be used to cover a greater chemical space compared to larger molecules. This increases the chance of including molecular frameworks within a screening library that complement the target binding site in an optimal manner.
‘Fragment’ compounds are characterised by their low molecular weight (classically, Mw < 300 Da), resulting in low complexity. Therefore, hit fragments bind to their target with weak affinity compared to ‘small molecule’ hits (Mw < 500 Da). However, the modest molecular size of fragments enhances their ability to access an optimal spatial orientation relative to binding features at the target. This presents a simpler starting point for drug design compared to larger, higher affinity hits, whose greater complexity may hinder the formation of optimally directed interactions towards each molecular recognition element at the target. These fragment hits are then grown or merged or linked with other hits in a process known as fragment optimisation. A second advantage of using fragments to provide a starting point is that the same number of compounds can be used to cover a greater chemical space compared to larger molecules. This increases the chance of including molecular frameworks within a screening library that complement the target binding site in an optimal manner.
Fragment libraries are built in a general or directed manner. In the general strategy, a specific set of ‘drug-likeness’ metrics is applied to sample the commercial pool while maximising the coverage of chemical space. The directed strategy involves using knowledge about the target to select compounds based on incorporating a specific desired pharmacophore or similarity to known binders of a particular target. However, this approach is likely to sacrifice chemical space coverage, due to conserving certain structural features across the library.
Fragment libraries are built in a general or directed manner. In the general strategy, a specific set of ‘drug-likeness’ metrics is applied to sample the commercial pool while maximising the coverage of chemical space. The directed strategy involves using knowledge about the target to select compounds based on incorporating a specific desired pharmacophore or similarity to known binders of a particular target. However, this approach is likely to sacrifice chemical space coverage, due to conserving certain structural features across the library.
The weak affinity of fragment hits means that sensitive biophysical techniques must be implemented to screen them. Some common methods include NMR, TDA, X-ray crystallography, and SPR.
The weak affinity of fragment hits means that sensitive biophysical techniques must be implemented to screen them. Some common methods include NMR, TDA, X-ray crystallography, and SPR.
Bioisosteer centric fragmentation
Bioisosteer centric fragmentation
We use known actives for target classes and even individual proteins to build fragment libraries. The high hit-rate for fragment libraries, coupled with population of known active moieties for a target aids in the discovery of medicinal chemistry starting points. Our custom software pipelines can evaluate a target space in relation to the known actives, how they fragment, the properties of resultant fragments, and commercial availability.
We use known actives for target classes and even individual proteins to build fragment libraries. The high hit-rate for fragment libraries, coupled with population of known active moieties for a target aids in the discovery of medicinal chemistry starting points. Our custom software pipelines can evaluate a target space in relation to the known actives, how they fragment, the properties of resultant fragments, and commercial availability.
Small molecule libraries
Small molecule libraries
The Auer group has access to a wide range of diverse commercial, proprietary and in-house small molecule libraries for hit finding. These libraries span known bioactives, fragment libraries based off of diverse hit-finding strategies (currently 7), diversity-based libraries, and target-class focused libraries.
The Auer group has access to a wide range of diverse commercial, proprietary and in-house small molecule libraries for hit finding. These libraries span known bioactives, fragment libraries based off of diverse hit-finding strategies (currently 7), diversity-based libraries, and target-class focused libraries.
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