Exploiting the Biophysical Sweet Spot in Fragment Screening

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Over the last twenty years, fragment-based drug design (FBDD) has emerged as a prominent strategy to identify innovative drug discovery hits. Unlike high throughput screening (HTS), which identifies moderate to high-affinity hits (often mirroring the size of a typical drug molecule), fragment screening scouts for much smaller molecule hits with weaker but leaner affinity to their biological target. The FBDD strategy has led to many drug discovery successes including four approved drugs, with another 40 under clinical investigation.

The principle of FBDD is that by screening lower molecular weight fragments a much smaller screening library is required to fully explore the receptor binding site. This affords economies of scale and time. Although the efficient sampling of the chemical universe is one of the key advantages of FBDD over HTS, it is often undermined by the excessive size of the molecules in fragment collections. Recent work has been published to address fragment obesity, but it remains a critical concern for most commercial libraries. 

Concomitantly, with the emergence of FBDD, many biophysical screening technologies have been developed to enable the detection of weak but lean binding events associated with small molecules. 

During this webinar, we will present how we aim to push the boundaries of fragment screening by designing a compound collection that efficiently samples the biophysically accessible chemical universe. We will describe the cheminformatic selection process employed to generate this high quality, atom-efficient, and highly diverse fragment library specifically tailored for biophysical screening. We will demonstrate that, unlike the majority of commercial fragment collections, our biophysical fragments match the physicochemical properties of fragment Hits identified over the last 20 years of FBDD. With our biophysical fragment collection in hand, we highlight key advantages associated with some of the most commonly used biophysical assay techniques and show how a suitable biophysical screening cascade can be developed to identify and prioritize the best fragment Hits, and in turn enable the most efficient Hit to Lead campaign.