Fragment-Based Drug Discovery (FBDD): Workflow, Benefits, and How It’s Shaping the Future of Drug Research

Over four decades since its conception in 1980, Fragment-Based Drug Discovery (FBDD) has emerged as an innovative and efficient approach to modern drug development, showing advantages over traditional high-throughput screening (HTS) methods. By focusing on smaller, simpler molecules, FBDD provides a foundation for developing novel therapeutics, especially for challenging previously “undruggable” targets.

Historically, FBDD has led to several milestone achievements in drug development, with eight FDA-approved drugs and more than 50 compounds currently in clinical stages. The first FDA-approved FBDD-derived drug, Zelboraf (vemurafenib, PLX4032), a BRAF inhibitor for melanoma developed by Plexxikon was initiated in 2005 and approved in 2011, demonstrating the efficiency of this approach in accelerating drug discovery timelines.

At o2h discovery, our integrated fragment-based screening platform combines biophysical and biochemical tools like the Biacore T200 Surface Plasmon Resonance (SPR) to enhance fragment screening, ensuring precision and efficiency in the FBDD workflow. This integrated approach accelerates hit identification, strengthens validation, and drives data-driven lead optimisation.

Understanding Fragment-Based Drug Discovery

Fragment-based drug discovery is a strategic approach to identifying potential start points for drug discovery projects by screening small, low-molecular-weight molecules termed fragments. These fragments bind to specific regions of a target protein, serving as a starting point for further expansion and optimisation. Unlike HTS, which screens vast libraries of large, complex drug-like molecules, FBDD relies on smaller libraries of simpler compounds. This ensures better “chemical space” coverage, as the smaller size and simplicity of fragments allow for a more comprehensive exploration of potential interactions with protein targets.

Although fragments tend to have lower affinities for their targets, they exhibit high “binding efficiency per atom,” making them ideal for designing highly potent and selective drug candidates. By integrating fragment screening with structural biology and medicinal chemistry, FBDD accelerates the path from hit discovery to lead optimisation, reducing costs, improving success rates, and broadening the reach of modern drug discovery.

FBDD Workflow: A Step-by-Step Approach

1. Fragment Library Design: The FBDD process begins with the careful selection or design of a diverse library of small molecule fragments. These fragments typically have low molecular weight (<300 Da) and high solubility, making them suitable starting points for drug discovery. Fragment libraries can be assembled from commercially available compounds, natural product extracts, or computationally designed molecules.
2. Fragment Screening: Fragments are screened against the target protein using a variety of biophysical techniques, including nuclear magnetic resonance (NMR) spectroscopy, X-ray crystallography, surface plasmon resonance (SPR), or isothermal titration calorimetry (ITC). These techniques enable researchers to detect weak binding interactions between fragments and target proteins.
3. Hit Identification and Validation: Promising Fragments that show binding affinity and ligand efficiency are confirmed using additional orthogonal test methods (biochemical and biophysical assays) to ensure they are genuine start points, termed hits. Hit compounds are evaluated further to ensure that they have the potential to modulate the desired biological pathway or target and offer scope to be elaborated and optimised.
4. Fragment Elaboration and Optimisation: Hit fragments are elaborated and optimized through a combination of rational drug design and medicinal chemistry techniques. By iteratively modifying the chemical structure of the fragments, researchers aim to enhance binding affinity, selectivity, and pharmacokinetic properties to develop lead compounds with drug-like characteristics. Structural information obtained from fragment screening facilitates rational drug design, guiding the optimisation process. Fragments are chemically optimized by adding or modifying functional groups to enhance binding strength, specificity, and drug-like properties.
5. Lead Optimisation: Lead compounds identified through FBDD undergo further optimisation to improve their drug-like properties, including potency, selectivity, solubility, and metabolic stability. This iterative process involves medicinal and computational chemistry, structural biology, broader biological and safety evaluation involving a range of preclinical studies to develop candidates suitable for clinical testing. The lead optimisation phase also involves exploration structure-activity relationships (SAR – making changes to molecules and observing the impact of profiles and properties), ADME profiling, and in-vivo efficacy studies to ensure pharmacokinetic and safety readiness for preclinical development.

Why is FBDD a Preferred Approach?

1. Efficient Use of Resources: FBDD focuses on screening smaller libraries of fragments, reducing the time and resources required for hit finding compared to traditional methods. Screening smaller sized molecules with more complimentary interactions with the target protein allows researchers to more efficiently explore a larger chemical space and increases the likelihood of identifying robust hits to rapidly explore their potential to generate high quality, novel lead compounds.
2. Higher Hit Rates: As fragments are smaller than traditional drug sized molecules, they have a higher probability of binding to key sites on a protein (albeit with weak/modest affinity). This increases the likelihood of identifying a range of hits providing scope and opportunities that can be further optimized into potent drug candidates. This enhances the success rate of FBDD campaigns, generally identifying lead compounds with greater therapeutic potential.
3. Improved Druggability: FBDD enables researchers to target challenging drug targets and protein-protein interactions that may be inaccessible using traditional methods. By focusing on smaller, more flexible molecules, FBDD can explore diverse chemical spaces and identify lead compounds with improved druggability.
4. Rational Drug Design: Structural information when available to support fragment screening facilitates rational drug design, allowing researchers to rapidly optimize fragment hits through structure-based approaches (either modifying the fragment to increase affinity, or allowing understanding of the best places to expand and grow the fragment to pick up additional new interactions to improve potency/affinity.

These benefits make Fragment-based drug discovery (FBDD) a game-changer, especially for developing therapeutics for “hard-to-drug” targets.

How o2h Discovery Supports FBDD Programs?

At o2h discovery, our scientists specialize in delivering tailored Fragment-Based Drug Discovery services, helping to identify, validate, and optimize fragments into high-quality leads. Our expert medicinal chemists, in collaboration with leading academic computational chemists, have meticulously designed a fragment library that ensures pharmacophore diversity, molecular complexity, and optimal physicochemical characteristics tailored for Fragment-Based Drug Discovery (FBDD). Our library is continually expanded to address any gaps, ensuring comprehensive coverage for FBDD applications, with >50% of the library being synthesized in house.

We leverage Biacore T200 Surface Plasmon Resonance (SPR) as a robust primary screening platform, enabling efficient evaluation of fragment binding at high micromolar concentrations. Fragments demonstrating confirmed activity are validated through orthogonal methods such as thermal stability (TS) assays.

Fragment-based drug discovery development strategy

Our SPR assay development team employs a precise experimental approach, including:

• Target immobilisation based on research precedents.
• Buffer scouting and binding studies using natural peptides or control compounds.
• Competitive and allosteric interaction studies.
• Sensorgram analysis for Kd, Kon, and Koff with optimized signal response.
• Protein stability and responsiveness evaluation.

Fragment screening identifies hits with >50% theoretical Rmax activity, followed by detailed kinetic characterization through:

• Specific vs. non-specific interaction discrimination.
• Counter screens using mutant proteins or controls.
• LC-MS validation for identity and purity.

We support orthogonal validation (e.g., fluorescence-based thermal stability) and evolve shortlisted fragments via:

• “SAR by catalogue” and analogue synthesis.
• Structural and computational insights for binding mode analysis.
• Mutagenesis studies to enhance SAR and lead optimisation.

Explore how o2h discovery applies Fragment-Based Drug Discovery using innovative platforms like SPR to identify and evolve fragment hits into promising lead candidates. Discover how our DYRK1A kinase case study demonstrates o2h discovery’s expertise in translating fragments into potent leads.

At o2h discovery, we are committed to supporting biotech companies in advancing their early-stage drug discovery programs. Our FBDD platform integrates advanced biophysical screening and medicinal chemistry expertise to enable precise hit identification, validation, and optimisation. Whether designing tailored fragment libraries or conducting hit-to-lead studies, we provide flexible and high-quality discovery solutions aligned with our clients’ objectives.

For further information or to explore collaboration opportunities, feel free to reach out to us at discovery@o2h.com.