7.5 Fragment-based drug discovery
6 min read•august 20, 2024
is an innovative approach that uses small molecular fragments as starting points for drug development. Unlike traditional , this method explores unique with target proteins, enabling the identification of novel chemical spaces.
The process involves designing , screening them against target proteins, and optimizing hits through growing, linking, or merging strategies. Various techniques like NMR, , and are used to detect and validate fragment binding, guiding rational drug design.
Fragment-based drug discovery overview
- Innovative approach to drug discovery that involves identifying small molecular fragments that bind to target proteins and using them as starting points for drug development
- Differs from traditional high-throughput screening (HTS) methods by using smaller, less complex molecules to probe protein binding sites
- Enables exploration of novel chemical space and identification of unique binding interactions that may be missed by larger, more drug-like compounds
Fragment libraries vs HTS libraries
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- Fragment libraries contain smaller molecules (typically <300 Da) with lower complexity compared to HTS libraries
- Fragments have higher probability of binding to target proteins due to their reduced size and complexity
- HTS libraries consist of larger, more drug-like compounds (>500 Da) that cover a broader range of chemical space but may miss unique binding interactions
Fragments as starting points
- Fragments that show binding to target proteins serve as starting points for drug development
- Optimization of fragment hits involves growing, linking, or merging to improve potency and
- Fragments provide a foundation for rational drug design by revealing key binding interactions and allowing for targeted modifications
Fragment screening techniques
- Various biophysical and biochemical methods are used to screen fragment libraries against target proteins
- Techniques include nuclear magnetic resonance (NMR), X-ray crystallography, surface plasmon resonance (SPR), , and
- Multiple orthogonal screening methods are often employed to validate fragment hits and provide complementary information on binding interactions
Fragment library design
- Careful design of fragment libraries is crucial for successful fragment-based drug discovery
- Libraries should balance diversity, physicochemical properties, and synthetic tractability
Rule of 3 criteria
- Guideline for designing fragment libraries based on favorable physicochemical properties
- Fragments should have molecular weight <300 Da, number of hydrogen bond donors and acceptors ≤3, and cLogP ≤3
- Rule of 3 helps ensure fragments have good solubility, permeability, and potential for optimization
Diversity vs focused libraries
- Diverse fragment libraries cover a wide range of chemical space and are useful for exploring novel binding interactions
- Focused libraries are designed to target specific protein classes or binding sites and may incorporate known
- Balance between diversity and focus depends on the specific drug discovery project and target of interest
Computational design approaches
- Computational methods can aid in the design and selection of fragment libraries
- Virtual screening techniques, such as docking and pharmacophore modeling, can prioritize fragments for experimental testing
- Cheminformatics tools can analyze and optimize library diversity, physicochemical properties, and synthetic feasibility
Fragment screening methods
- Various biophysical and biochemical techniques are used to screen fragment libraries against target proteins
- Each method has its strengths and limitations, and a combination of techniques is often employed for robust
NMR-based screening
- is a powerful tool for detecting weak protein-fragment interactions
- Techniques such as saturation transfer difference (STD) and WaterLOGSY can identify fragment binding without requiring protein labeling
- NMR provides information on binding site location and can guide fragment optimization
X-ray crystallography screening
- X-ray crystallography allows direct visualization of fragment binding modes in complex with the target protein
- Provides high-resolution structural information on key interactions and guides rational fragment optimization
- Requires protein crystallization and can be time-consuming and challenging for some targets
Surface plasmon resonance
- SPR is a label-free technique that measures real-time binding interactions between fragments and immobilized target proteins
- Provides kinetic and affinity data on fragment binding
- Useful for ranking fragment hits and assessing structure-activity relationships during optimization
Mass spectrometry techniques
- Mass spectrometry-based methods, such as native mass spectrometry and affinity selection mass spectrometry, can detect protein-fragment complexes
- Provides information on binding stoichiometry and can identify covalent fragment binders
- High sensitivity and throughput make mass spectrometry a valuable tool for
Thermal shift assays
- Thermal shift assays, also known as differential scanning fluorimetry (DSF), measure changes in protein thermal stability upon fragment binding
- Fragments that bind to and stabilize the target protein cause a shift in its melting temperature
- High-throughput and inexpensive method for screening large fragment libraries
Fragment optimization strategies
- Once fragment hits are identified, they need to be optimized to improve potency, selectivity, and drug-like properties
- Several strategies are employed to transform fragments into lead compounds
Fragment growing
- Involves adding functional groups or small moieties to the fragment hit to increase interactions with the target protein
- Guided by structural information from X-ray crystallography or NMR to identify growth vectors
- Aim is to improve potency while maintaining favorable physicochemical properties
Fragment linking
- Involves connecting two or more fragment hits that bind to adjacent sites on the target protein
- Requires structural information to guide the design of suitable linkers
- Can result in significant potency gains but may be synthetically challenging
Fragment merging
- Involves combining structural features of multiple fragment hits into a single molecule
- Useful when fragments bind to overlapping sites or when linking is not feasible
- Requires careful design to maintain favorable interactions and physicochemical properties
Challenges in fragment-based drug discovery
- Despite its advantages, fragment-based drug discovery also presents several challenges that need to be addressed
Weak initial binding affinities
- Fragments often have weak binding affinities (typically in the micromolar to millimolar range) due to their small size
- Requires sensitive screening methods and careful validation to distinguish true hits from false positives
- Optimization of weak fragment hits can be challenging and time-consuming
Synthetic feasibility of optimized fragments
- Fragment optimization often involves adding complexity to the initial fragment hit
- Resulting compounds may be synthetically challenging or require lengthy synthetic routes
- Balancing potency gains with synthetic accessibility is crucial for successful lead development
Intellectual property considerations
- Fragments are often less novel and may have broader patent coverage compared to larger, more complex compounds
- Careful analysis of existing patents and strategic design of optimized fragments is necessary to ensure freedom to operate
- Collaborative partnerships and licensing agreements may be required to navigate intellectual property landscapes
Success stories of fragment-based drugs
- Fragment-based drug discovery has led to the development of several approved drugs and clinical candidates
- Examples demonstrate the potential of this approach for tackling challenging targets and discovering novel therapeutics
Vemurafenib for melanoma treatment
- is a selective inhibitor of mutant BRAF kinase, which is a driver of melanoma growth
- Developed using fragment-based methods, starting from a weakly binding fragment hit
- Approved by the FDA in 2011 for the treatment of metastatic or unresectable melanoma with BRAF V600E mutation
Venetoclax for chronic lymphocytic leukemia
- is a selective inhibitor of the anti-apoptotic protein BCL-2, which is overexpressed in chronic lymphocytic leukemia (CLL)
- Discovered using fragment-based screening and structure-guided optimization
- Approved by the FDA in 2016 for the treatment of CLL in patients with 17p deletion
AT7519 for cancer therapy
- is a potent inhibitor of cyclin-dependent kinases (CDKs), which are involved in cell cycle regulation and cancer progression
- Identified using fragment-based methods and optimized for potency and selectivity
- Currently in clinical trials for various cancer indications, including leukemia and solid tumors
Integration with other drug discovery approaches
- Fragment-based drug discovery can be integrated with other computational and experimental methods to enhance its effectiveness
Combining with structure-based drug design
- Structural information from X-ray crystallography or NMR can guide fragment optimization and lead design
- Iterative cycles of structure determination and rational design can accelerate the drug discovery process
- Molecular modeling and docking studies can complement experimental data and guide fragment selection and optimization
Synergy with virtual screening methods
- Virtual screening techniques, such as ligand-based and structure-based methods, can prioritize fragments for experimental testing
- Computational methods can explore larger chemical spaces and identify novel fragments with desired properties
- Integration of virtual screening with fragment-based methods can improve hit rates and reduce experimental costs
Complementing high-throughput screening
- Fragment-based methods can be used in parallel with or as a follow-up to high-throughput screening campaigns
- Fragments can explore chemical space not covered by larger HTS libraries and identify novel binding modes
- Combining hits from both approaches can provide a more diverse set of starting points for
Key Terms to Review (29)
AstraZeneca: AstraZeneca is a global biopharmaceutical company known for its innovative drug development and research efforts, particularly in areas like oncology, cardiovascular diseases, and respiratory conditions. The company has made significant contributions to fragment-based drug discovery, a method that utilizes small molecular fragments as starting points for developing new therapeutic agents.
At7519: at7519 is a small molecule inhibitor of cyclin-dependent kinases (CDKs), particularly CDK2 and CDK9, which play crucial roles in cell cycle regulation and transcription. It has been explored for its potential in cancer therapy due to its ability to disrupt the proliferation of cancer cells by interfering with cell cycle progression and transcriptional regulation.
Binding interactions: Binding interactions refer to the various forces and mechanisms through which a molecule, such as a drug, attaches to its target, typically a protein or enzyme. These interactions are crucial in determining the efficacy and specificity of a drug, influencing how well it can modulate biological processes. Understanding these interactions is essential for optimizing drug design and developing therapeutics through techniques like fragment-based drug discovery.
Bioavailability: Bioavailability refers to the proportion of a drug or substance that enters the systemic circulation when it is introduced into the body, making it available for therapeutic effect. This concept is crucial because it influences how effectively a drug performs in its intended role, impacting factors like dose-response relationships and absorption rates.
Fragment growing: Fragment growing is a technique used in drug discovery where small chemical fragments are progressively expanded or modified to develop more potent and selective drug candidates. This process allows chemists to build upon initial fragment hits, optimizing their interactions with biological targets through iterative design and synthesis. The technique relies on structural information, often obtained from techniques like X-ray crystallography, to guide the modification of fragments into more complex molecules that can effectively bind to the desired target.
Fragment libraries: Fragment libraries are collections of small chemical compounds or molecular fragments that serve as starting points for drug discovery. These fragments are typically low molecular weight and can bind to biological targets, providing essential structural information that can be optimized into larger, more complex drug candidates. The use of fragment libraries is crucial in fragment-based drug discovery, as they allow researchers to explore a broader chemical space efficiently and identify potential lead compounds.
Fragment linking: Fragment linking is a technique used in drug discovery where small chemical fragments are combined to create larger, more complex molecules that can potentially bind to biological targets. This process allows researchers to identify promising lead compounds by connecting smaller, simpler structures, enhancing their ability to interact with specific proteins or enzymes.
Fragment merging: Fragment merging is a computational and experimental technique used in drug discovery that involves combining two or more small molecular fragments to create a larger, more complex compound that has improved binding affinity to a target protein. This approach capitalizes on the idea that smaller fragments can be optimized and then merged to form a more potent drug candidate, often resulting in higher specificity and fewer off-target effects. By systematically analyzing the binding interactions, researchers can design better candidates with enhanced biological activity.
Fragment screening: Fragment screening is a drug discovery technique that involves the identification of small chemical fragments that can bind to a target protein, potentially leading to the development of new therapeutic agents. This method focuses on using low molecular weight compounds, which allows for the exploration of a wider chemical space and increases the chances of finding hits that can be optimized into lead compounds for drug development.
Fragment-based drug discovery: Fragment-based drug discovery is a method used to identify small chemical fragments that can bind to biological targets, forming the basis for developing new drugs. This approach allows researchers to explore a vast chemical space efficiently, leading to the identification of potential lead compounds with improved binding affinities and selectivities during the drug development process.
High-throughput screening: High-throughput screening (HTS) is a method used in drug discovery to quickly test thousands to millions of compounds for their biological activity against specific targets. This process allows researchers to identify potential lead compounds efficiently, which can then be further optimized and developed into drugs. By automating the testing and analysis processes, HTS enables faster progression through the phases of target identification, lead discovery, and preclinical development.
Hit Identification: Hit identification is the process of finding potential drug candidates, or 'hits', that can interact with a biological target to affect its function. This initial step is crucial in drug discovery as it sets the foundation for lead optimization and further development. It involves screening compounds from various libraries or collections to identify those that show desired biological activity against the target, often paving the way for the next phases of drug development.
In silico modeling: In silico modeling refers to the use of computer simulations and computational techniques to predict and analyze biological processes, molecular interactions, and drug behaviors. This approach is integral for streamlining drug discovery and development, allowing scientists to virtually assess how compounds interact with biological targets and to predict their pharmacokinetic properties without the need for extensive laboratory experiments.
Lead Optimization: Lead optimization is the process of refining and improving the properties of drug candidates, known as leads, to enhance their efficacy, selectivity, and safety before they enter clinical trials. This phase involves systematic modification of chemical structures based on various criteria, which helps identify the best candidate for further development and testing.
Mass Spectrometry: Mass spectrometry is an analytical technique used to measure the mass-to-charge ratio of ions, allowing for the identification and quantification of molecules in a sample. This method is essential in various fields for characterizing chemical compounds, analyzing biomolecules, and determining molecular structures, making it invaluable in early drug development, chemical property assessments, and exploring complex mixtures such as natural products.
Nmr spectroscopy: NMR spectroscopy, or nuclear magnetic resonance spectroscopy, is a powerful analytical technique used to determine the structure of organic compounds by observing the magnetic properties of atomic nuclei. This method provides detailed information about the molecular structure, dynamics, and environment of atoms, making it an essential tool in various fields including medicinal chemistry, where understanding molecular interactions is crucial for drug development and design.
Off-target effects: Off-target effects refer to unintended interactions of a drug or therapeutic agent with targets other than the intended biological target. These interactions can lead to unexpected biological responses, including toxicity or reduced efficacy, complicating the drug development process. Recognizing and minimizing off-target effects is crucial for ensuring drug safety and effectiveness, impacting various stages from identifying potential targets to assessing adverse drug reactions.
Privileged scaffolds: Privileged scaffolds are chemical frameworks that provide a versatile platform for the design and development of bioactive compounds. These structures have the ability to interact with multiple biological targets, making them invaluable in drug discovery efforts, particularly in fragment-based drug discovery, where smaller molecular fragments are optimized into larger, more complex drug candidates.
Rule of 3 Criteria: The Rule of 3 Criteria is a guideline used in fragment-based drug discovery to identify and prioritize small chemical fragments that can effectively bind to biological targets. It emphasizes the importance of selecting fragments that possess certain physicochemical properties, such as molecular weight, lipophilicity, and hydrogen bond donors/acceptors. This rule helps researchers focus on fragments with optimal characteristics that are more likely to lead to successful drug candidates.
SAR analysis: SAR analysis, or Structure-Activity Relationship analysis, is a method used to understand the relationship between the chemical structure of a compound and its biological activity. This approach is crucial in medicinal chemistry as it helps identify the molecular features that influence the pharmacological properties of drug candidates, guiding the optimization of lead compounds during drug discovery.
Selectivity: Selectivity refers to the ability of a drug or compound to preferentially bind to a specific target, such as a receptor or enzyme, while minimizing interactions with other targets. This characteristic is crucial for enhancing therapeutic efficacy and reducing side effects, making it a central concept in drug design and optimization processes. Understanding selectivity is essential for developing drugs that provide maximum therapeutic benefit while limiting undesirable effects on non-target systems.
Solubility issues: Solubility issues refer to the challenges faced when a substance has limited or inadequate solubility in a given solvent, which can affect its bioavailability and effectiveness as a drug. In drug discovery and delivery, these issues are critical because they influence how well a drug can be absorbed in the body and how efficiently it interacts with its target. Understanding solubility is essential for optimizing drug formulations to ensure that therapeutic agents can reach their desired concentration in the bloodstream and tissues.
Structure-guided design: Structure-guided design is an approach in drug discovery that utilizes the three-dimensional structure of a biological target, typically a protein, to inform and optimize the development of new therapeutic compounds. This method relies on detailed knowledge of the target's molecular architecture to design molecules that can interact effectively, improving the chances of discovering potent and selective drugs.
Surface Plasmon Resonance: Surface plasmon resonance (SPR) is an optical technique that measures the refractive index near the surface of a sensor chip, typically used to study biomolecular interactions in real-time. By shining light onto a metal surface, such as gold or silver, it excites surface plasmons, which are collective oscillations of electrons at the surface, and any changes in the interaction can be detected as shifts in the light reflected from the surface. This method is particularly valuable in assessing binding kinetics and affinities of ligands and fragments during drug design and discovery processes.
Thermal shift assays: Thermal shift assays are a biochemical technique used to evaluate the stability of proteins in response to temperature changes, often employed in drug discovery. This method involves monitoring the melting temperature of a protein, which shifts in the presence of ligands or potential drug candidates, indicating binding events. Such assays are particularly relevant in fragment-based drug discovery as they help identify promising compounds that stabilize target proteins.
UCB Pharma: UCB Pharma is a global biopharmaceutical company based in Belgium, focused on the discovery and development of innovative medicines for severe diseases, particularly in neurology and immunology. Its commitment to research and development has led to significant advancements in therapies, contributing to the field of fragment-based drug discovery by optimizing small molecules that target specific proteins.
Vemurafenib: Vemurafenib is a targeted cancer therapy that inhibits the activity of mutant BRAF V600E kinases, which are involved in cell signaling pathways that promote tumor growth in melanoma and other cancers. This drug exemplifies how fragment-based drug discovery can lead to the development of small molecules that specifically target these mutations, thereby improving treatment efficacy and minimizing side effects compared to traditional chemotherapy.
Venetoclax: Venetoclax is a targeted cancer therapy drug that specifically inhibits the B-cell lymphoma 2 (BCL-2) protein, which is often overexpressed in certain types of blood cancers, particularly chronic lymphocytic leukemia (CLL) and some non-Hodgkin lymphomas. By blocking BCL-2, venetoclax promotes apoptosis in cancer cells, making it an important example of how fragment-based drug discovery can lead to effective therapies for challenging diseases.
X-ray crystallography: X-ray crystallography is a powerful analytical technique used to determine the atomic and molecular structure of a crystal by diffracting X-ray beams through it. This method reveals the arrangement of atoms within a molecule, providing critical insights into the three-dimensional structures of biological macromolecules like proteins and nucleic acids. The ability to visualize these structures is essential for understanding interactions at the molecular level, which is crucial for various scientific applications, including the design of new drugs, discovery of novel drug fragments, and modeling pharmacophores.