Fragment screening is a powerful method for identifying chemical starting points and developing them into small molecules therapeutics. Even in the absence of structural information using label-free biosensing fragments hits were developed into drug-like compounds. Fragment screening was successful where other methods failed. Nevertheless, fragment screening provides its own challenges.
Fragments often bind weakly and require assays with sufficient sensitivity to detect weak interactions. For many label-free biophysical methods, the signal level is proportional to the molecular weight of the screened compounds and fragments are small by design. Additionally, for the surfaced-based biosensing method, it is difficult to immobilize the target at a high density while preserving its function. Aggregation is also common in fragment screening which can lead to false positive results. All these factors make it difficult to set up biophysical assays for fragments screening especially when targeting membrane proteins.
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