Direct-to-Biology (D2B) is changing how medicinal chemistry teams generate data, enabling crude reaction mixtures to be tested directly in biological assays and dramatically shortening the design-make-test-analyze cycle. In this ask the expert article, we spoke with Euan Fordyce, Associate Director Chemistry at Sygnature Discovery, about where D2B delivers the most value, its current limitations, and where the approach is headed next.

Biocompare: What is Direct-to-Biology (D2B) and how does it differ from a traditional medicinal chemistry workflow?

Euan: “Direct-to-Biology (D2B), a term coined by scientists at GSK in 2021, refers to the direct biological profiling of crude reaction mixtures in assays without prior purification. This approach typically leverages high-throughput chemistry, with reactions conducted in 96- or 384-well plate formats. By eliminating the need for compound purification, it significantly reduces the time from reaction setup to generation of key assay endpoint data. Additional efficiencies are gained through performing reactions at the nanoscale, which minimizes the amount of building blocks required. Collectively, these advantages compress project timelines, enabling faster decision-making and ultimately accelerating the delivery of new medicines to patients.”

Biocompare: What types of projects or target classes have you found benefit most from a D2B approach—and are there situations where you'd actively recommend against using it?

Euan: “D2B has been successfully applied across a broad range of projects, spanning traditional small-molecule inhibitors, covalent modifiers, and emerging modalities such as heterobifunctional degraders and molecular glues. While, in principle, this approach can be applied at any stage from hit identification through to lead optimisation, its greatest impact is realized in areas where existing knowledge is limited. For example, at the transition from hit identification to hit-to-lead, where experimental data and SAR are often sparse, D2B enables the rapid and cost-effective generation of relevant data. It has also proven particularly valuable in challenging project contexts where conventional modelling approaches are less effective, such as with molecular glues. In these cases, the speed and throughput of D2B have been instrumental in identifying novel chemical starting points.”

Biocompare: What kind of throughput and cycle-time gains have you typically seen with D2B compared to a conventional design-make-test-analyze cycle, and how does that translate into project timelines or cost savings for clients?

Euan: “Publicly available data suggest that D2B workflows, encompassing synthesis, analysis, and testing, can be executed in a 384-well plate format in under two weeks, requiring less than 200 mg of building blocks. In some cases, this timeline can be reduced to just a few days while still generating a substantial volume of data. In a recent D2B-enabled project, we were able to deliver a preclinical candidate for our customers in just 18 months, compared to an industry average of 4 years. By comparison, a conventional library of 48 compounds typically requires approximately 1.5 g of starting material and takes 2–4 weeks to progress from synthesis to assay readout (external data). As synthetic chemistry often represents one of the most resource-intensive aspects of the discovery phase of drug discovery, reducing the time needed to generate critical data can have a significant impact on overall project costs, ultimately delivering meaningful savings to clients.”

Biocompare: What are the main limitations of D2B today and where do you see the technology heading over the next few years?

Euan: “If your chemistry is not well suited to array-based approaches, D2B is unlikely to be effective. Another key consideration is whether the assay endpoint is influenced by components in the crude reaction mixture beyond the compound of interest. In some cases, these challenges can be mitigated through partial purification strategies, although this typically requires specialized equipment compatible with plate-based chemistry. For biochemical and cellular assays, achieving high reaction conversion is particularly important to ensure meaningful data. However, techniques such as off-rate screening (ORS) can help to address some of these limitations. While there is an increased risk of false positives or negatives with D2B, a pragmatic approach, recognizing that gains in speed and throughput may outweigh the loss of full data granularity, can make this a highly powerful methodology.
“Looking ahead, D2B is likely to see broader adoption as one of several complementary tools to accelerate drug discovery. Furthermore, the use of crude reaction mixtures may extend beyond measuring affinity and efficacy to include physicochemical and ADME properties, and even structural biology. Indeed, emerging evidence suggests that crude mixtures can be applied in crystallography, where the protein active site effectively selects for active components within complex mixtures. This Direct-to-Crystal (D2C) approach has the potential to further enhance the value and impact of this evolving area of drug discovery."