Fragment-Based Screening in Drug Discovery
Fragment-based drug discovery has established itself as a key approach within the field.
Rather than being viewed as an alternative starting point when traditional methods fail, fragment-based drug discovery (FBDD) is now frequently deployed as a first-line strategy. Advances have driven FBDD forward, facilitating exploration of increasingly complex biological targets.
Content
What is fragment-based drug discovery and why is it useful?
Size matters…
Establishing fragment-based screening approaches
- Theoretical basis for fragment-based drug discovery
- Fragment libraries and chemical space coverage
- Lead optimization strategies
- Fragment merging, linking, and growing
Drugs derived from fragment-based methods
Strength in numbers: Combining fragment-based methods with other approaches
Computational and structural biology integration in fragment-based drug discovery
Fragment-based drug discovery: What does the future hold?
What is fragment-based drug discovery and why is it useful?
FBDD starts with a collection of very small compounds, typically < 300 Daltons in weight. It relies on the concept that low-molecular-weight compounds can serve as efficient probes of protein binding sites. Although fragments generally bind with low affinity, they exhibit high ligand efficiency, meaning they bind effectively relative to their size.
Ligand efficiency explained
Ligand efficiency describes a compound's binding affinity, or strength, relative to its size. In small-molecule or fragment-based drug discovery, high ligand efficiency is crucial to ensure that small compounds form high-quality interactions, making efficient use of their small size.
The impact is tangible, with smaller compound sizes reducing the number of possible fragments compared to other drug discovery approaches, such as high-throughput screening (HTS).
To put it into perspective, it is estimated that there are more possible small drug-like molecules than there are stars in the universe! In contrast, fragment libraries are composed of just a few thousand minuscule molecules.
Following identification, suitable small chemical “building blocks” can be optimized into higher-affinity ligands.
Size matters…
The larger the molecule, the more complex it becomes. The greater the molecular complexity, the greater the probability of interactions with a protein target—interactions that may not always be favorable.
Small fragments form fewer interactions with a protein target, and are therefore expected to bind to more sites across targets, translating to a greater number of "hits" (Figure 1).
The size of fragment-based compound libraries in comparison to those generated by other approaches meant that initially, fragment techniques were largely pursued by small biotech companies. Prof. Roderick Hubbard, Structural Biology Lab, University of York, UK, explained: “It took some time for the majority of medicinal chemists to realize that starting with a small, weak affinity hit is preferable to working with a larger, more potent compound.”
Figure 1: Comparison of HTS and fragment binding to a protein target. Credit: Technology Networks.
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Establishing fragment-based screening approaches
Prof. György Miklós Keserű, principal investigator, Medicinal Chemistry Research Group at the RCNS-HAS, Hungary, proposed that: “…there were many important contributions that resulted in the development of the FBDD approach into a validated strategy for both academia and pharma. Concerted efforts by the founders and practitioners of FBDD have solved many problems including; library design, screening, and fragment optimization.”
Theoretical basis for fragment-based drug discovery
Long before FBDD was physically put into practice, Jencks published on the theoretical basis for FBDD. “The idea of using small pieces of chemistry which are found to bind to the active site of a protein was established in the mid-1980s by the computational- and (subsequently in the early 1990s) structural biology community,” said Hubbard.
This theoretical background was supplemented in 1984 when Andrews et al. proposed that individual functional groups contributed intrinsic binding energies that could be used to determine the ‘goodness of fit’ of a drug to its target.
“Fragment-based methods were first practically applied to the drug discovery field by the group of Fesik and Hajduk at Abbott in 1996,” commented Hubbard. Scientists used a nuclear magnetic resonance (NMR)-based method to identify fragments that could bind to proximal subsites of the target protein—fragments that were then optimized.
Several alternative approaches have since been developed, ranging from functional and biophysical, to computational in nature (Table 1).
Table 1: Fragment-based screening methods for drug discovery.
| Method | Description | Category | Status |
| NMR spectroscopy | Detects fragment binding by changes in nuclear spin environments, enabling the identification of weak binders and the mapping of binding sites. | Biophysical | Core |
| X-ray crystallography | Determines high-resolution 3D structures of fragment–protein complexes, directly revealing binding poses. | Structural | Core |
| Surface plasmon resonance spectroscopy | Detects binding by measuring changes in refractive index as fragments interact with the target, which is immobilized on a metal chip. | Biophysical | Core |
| Functional/biochemical assays | Measure biological activity (e.g., enzymatic reactions) to confirm functional relevance of fragment binding. | Biochemical | Core |
| Virtual screening | Uses computational approaches to predict fragment binding modes and assess interactions with protein targets. | Computational | Core |
| Isothermal titration calorimetry | Measures heat changes during fragment–protein binding. | Biophysical | Advanced/supporting |
| Thermal shift assays | Detects ligand-induced stabilization by monitoring changes in protein melting temperature. | Biophysical | Advanced/supporting |
| Mass spectrometry-based screening | Identifies fragment binding through detection of mass shifts in fragment–protein complexes. | Biophysical | Advanced/supporting |
Fragment libraries and chemical space coverage
Fragment libraries are central to fragment-based screening strategies. Libraries may be diversity-oriented by design, maximizing broad and structurally varied coverage of chemical space, or target-focused, aiming to probe a defined site.
Chemical space
In drug discovery, chemical space describes the theoretical and virtually infinite set of all possible small organic molecules, encompassing both biologically active and inactive structures, as well as synthetically accessible and inaccessible molecules.
Lead optimization strategies
Effective fragment optimization often involves two key steps. Firstly, co-structures of fragments bound to target proteins are required to select the most promising hits, which can then be considered for development into a lead candidate. The second step involves performing several biophysical and biochemical assays to track fragment potency and efficacy. These additional assays complement previously acquired data from the initial biophysical studies for rational design.
“Fragment starting points generally have a ‘good’ physchem profile – they bind to protein hot spots and there is potential to optimize them rationally using structural information and ligand efficiency metrics,” noted Keserű.
Fragment merging, linking, and growing
There are three main methods used for fragment elaboration (Figure 2). The first is "linking" whereby non-overlapping fragments that bind at different protein target sites are linked together to produce a novel chemical series. Another is "merging", which involves combining the common structural parts of overlapping fragments that complex with the target protein. Thirdly is fragment "growing" which involves building "sensible chemistry" around a single fragment hit.
Figure 2: A graphic illustrating fragment linking, merging, and growing in fragment elaboration. Credit: AI-generated image created using Microsoft Copilot (2026).
Drugs derived from fragment-based methods
YOUTUBE VIDEO: Understanding Fragment-Based Drug Discovery. Credit: Technology Networks via YouTube.
“The successes of the mid-to-late 2000s led to the adoption of fragment-based methods across most companies and there are now many published success stories of advancing from a weak, mM fragment hit to a potent, nM drug candidate for “conventional” drug targets such as kinases and most enzymes,” Hubbard explains.
Today, cancer therapies are among the successful developments resulting from fragment-based research (Table 2).
Table 2: Examples of FBDD-derived drugs. Credit: Technology Networks.
Strength in numbers: Combining fragment-based methods with other approaches
Fragment-based screening and HTS were historically viewed as competing strategies in early-stage drug discovery. However, contemporary workflows increasingly integrate multiple screening modalities into unified, data-driven discovery pipelines.
“Although fragment screening was often used as a ‘backup’, for targets without HTS hits, nowadays fragment screening and HTS are applied in parallel,” noted Keserű.
Computational and structural biology integration in fragment-based drug discovery
Modern fragment-based workflows are often integrated with computational modelling and structural biology. Molecular docking and dynamics simulations are frequently used to predict fragment binding poses, prioritize fragment libraries before screening, and guide fragment optimization.
Structural biology is central to fragment-based screening, providing insights into binding pockets, interactions, and resulting effects.
Additionally, cryo-electron microscopy is increasingly applied to larger protein complexes that are difficult to crystallize, expanding the applicability of FBDD to previously intractable targets.
Advantages and limitations of fragment-based screening
Fragment-based screening offers several advantages over traditional screening approaches, particularly in early-stage drug discovery.
Advantages:
- High ligand efficiency starting points
- Strong structural interpretability
- Efficient coverage of chemical space with small libraries
- Reduced screening costs compared to HTS
- Compatibility with multiple target classes
Limitations:
- Requires sensitive biophysical instrumentation
- Weak binding complicates initial detection
- Optimization can be chemically intensive
- Dependence on structural biology
- Challenges with flexible or membrane proteins
Fragment-based drug discovery: What does the future hold?
FBDD has evolved from an emerging methodology into a well-established and widely adopted strategy within early-stage drug discovery. Advances have enabled exploration of complex targets while computational approaches, including AI and machine learning, have become integral, expanding accessible chemical space.
Despite these advances, key challenges remain. Successful implementation of FBDD depends on the availability of high-quality protein constructs and robust, well-characterized assays capable of detecting weak binding events.
Developments are expected to streamline fragment-to-lead optimization and extend the applicability of fragment-based approaches across a broader range of therapeutic areas.
In this context, fragment-based drug discovery is positioned not only as a mature and reliable methodology but also as a continually evolving platform that is redefining how early-stage drug discovery is approached in modern research.
This content includes text that has been created with the assistance of generative AI and has undergone editorial review before publishing. Technology Networks' AI policy can be found here.
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