Fragment Based Screening (FBS)

Scientists at iNovacia are pioneers and have a long experience in fragment based screening. We have close to 1,000 fragments in a carefully designed screening library and access to the Asinex “Rule-of-three” compound libraries comprising in total ca 5,000 small compounds.

iNovacia can perform fragment based screening either as a complement or an alternative to conventional HTS for soluble targets. In the fragment approach, the screened compounds are smaller, have less functionality and are correspondingly weaker binders (µM – mM affinities) than most hits from HTS. However, the number of compounds screened is much smaller (typically <1,000) since low complexity compounds have a much higher probability of matching a target protein binding site. Further, a high proportion of the atoms in a fragment hit are directly involved in the desired protein-binding interaction, i.e. they are efficient binders. Starting the chemical optimisation stage with an efficiently binding low-molecular weight fragment is likely to produce leads with molecular masses that are “lead-like”.

Fragment based screening utilises generic binding assays such as NMR spectroscopy techniques which are suitable to detect weak binders. These techniques require no assay development and can thus be employed immediately in a very early stage of drug discovery projects, as soon as 1-2 mg of target protein has been produced. Development of the fragment hits will be much facilitated if information on the binding mode of the fragments is obtained. As a first step, competition experiments using earlier known binders are employed to confirm binding to the desired binding site. Fragments are then ranked with respect to binding affinity and/or potency, the latter requires a biochemical activity assay which does not have to be in HTS format. Attempts to obtain high resolution crystal structures of fragment-target complexes should be initiated as early as possible. Despite the low affinity, highly resolved complex structures can often be obtained due to the high solubility and specific binding of the fragments.