Fragment based drug design

Unit-4 (b)

PRESENTED BY
MALSAWMPUII
M.PHARM, 2ND SEMESTER
PHARMACEUTICAL CHEMISTRY DIVISION
RIPANS
Introduction
• Fragment-based drug design (FBDD) is a powerful approach used in drug
discovery and development to identify and optimize small, fragment-sized
molecules into potent and selective drug candidates.
• It has gained significant attention and popularity in the pharmaceutical industry
due to its ability to overcome some of the challenges associated with traditional
high-throughput screening (HTS) methods.
• In traditional high-throughput screening (HTS), large collections of compounds
are tested to find ones that interact with a biological target. While HTS can
identify potential drug candidates, it has drawbacks like low selectivity and the
need for many chemical modifications.
• In contrast, Fragment-Based Drug Design (FBDD) takes a smarter approach by
using small molecular fragments that bind to a target. These fragments are then
combined or modified to create more effective and selective drugs. This method
helps discover new drugs more efficiently and with fewer chemical changes.

Fragment-based Drug Design

What is fragment?
• Small organic molecules with a low molecular weight and size are known as fragments.
The principle behind FBDD is to find small chemical fragments that bind to biological
targets weakly, then expand or combine them to create a lead with a larger affinity. These
pieces bind to the target protein in various locations. A lead molecule is created when the
fragments mix or link with one another after binding.
The three-rule test determines whether a compound is a fragment.
1. Molecular mass less than 300 da
2. When Log P is less than3.
3. There are at least three hydrogen bond donors and acceptors.
• With the advancement of structural biology and the creation of new screening
techniques, FBDD has been easily continued and is now a significant component of
target-based drug discovery. To create more active molecules, fragments within protein
binding pockets can be expanded, connected, or combined once they have been found.
Key Steps in Fragment-Based Drug Design (FBDD)
Step 1: Identify the Target Protein

The first step in FBDD is selecting the biological target that plays a key role in the disease process.
This target can be an enzyme, receptor, or protein-protein interaction that is involved in the disease
mechanism. Once the target is identified, researchers obtain structural information about it, either
from experimental methods like X-ray crystallography or NMR spectroscopy, or through
computational approaches like homology modeling.

Step 2: Fragment Library Selection

The next step is selecting a library of molecular fragments to screen against the target. These
fragments are typically small molecules that are designed to interact with a protein’s binding site.
Fragment libraries are usually composed of low molecular weight compounds that are highly
diverse in structure, and they serve as a starting point for identifying potential lead compounds.
Researchers carefully choose fragments with high diversity to ensure that they cover a wide range
of binding modes and interactions.
Step 3: Screen the Fragment Library

• Once the fragment library is ready, it is screened against the target protein to identify those
fragments that bind effectively. Screening can be done using techniques such as high-
throughput screening (HTS), surface plasmon resonance (SPR), or X-ray crystallography.
The goal is to find fragments that bind to the target with reasonable affinity and
specificity. These hits serve as the starting point for lead development.

Step 4: Validate Fragment Binding

• After identifying the binding fragments, the next step is to validate their interaction with
the target protein. This is done by conducting additional experiments, such as in vitro
assays, to confirm that the fragments bind specifically to the target and not to off-target
proteins. Validation also involves evaluating the binding affinity and the nature of the
interactions between the fragment and the target’s binding site.
Step 5: Optimize the Fragments

• Once the binding fragments are validated, the next step is to optimize them into more potent
compounds. Fragment optimization involves growing or linking the fragments to create larger
molecules with improved binding affinity, selectivity, and drug-like properties. Medicinal
chemistry techniques are employed to modify the fragment’s structure, while structure-activity
relationship (SAR) analysis helps to identify the best structural modifications.

Step 6: Lead Optimization

• After optimizing the fragments, the next step is to refine the resulting compounds further. This
involves assessing their ADMET testing properties, ensuring they are pharmacologically
suitable for development. Researchers may also perform additional optimization cycles to
improve the compound’s bioavailability, stability, and safety profile. The goal is to develop a
compound with the ideal combination of potency, selectivity, and pharmacokinetic properties.
Applications of Fragment-based Drug Design:
• Kinase Inhibitors: FBDD has been successful in identifying potent and selective kinase
inhibitors for the treatment of various cancers and inflammatory diseases. Examples include
vemurafenib and foretinib.
• Protein-Protein Interactions: FBDD is increasingly being applied to target protein-protein
interactions implicated in diseases such as cancer and neurodegenerative disorders. By disrupting
these interactions, FBDD offers new therapeutic opportunities.
• Epigenetic Targets: FBDD has shown promise in targeting epigenetic enzymes, such as histone
deacetylases (HDACs) and bromodomain-containing proteins (BETs), involved in the regulation
of gene expression. These targets are of interest in cancer and other diseases.
• Antibacterial Agents: FBDD is being utilized to discover novel antibiotics to combat drug-
resistant bacterial infections. By targeting essential bacterial proteins, such as enzymes involved
in cell wall biosynthesis or DNA replication, FBDD offers a strategy to overcome antibiotic
resistance.
Limitations

• The variety of protein families that can be targeted by FBDD is one possible
drawback. The abundance of high-resolution protein structures is reflected in the
numerous instances of kinases and other enzymes as well as PPIs; yet, FBDD has
only targeted a small number of membrane proteins. This could soon change, as
advances in transmembrane proteins have been made possible by cryo-electron
microscopy. Since fragment binding has been demonstrated by the method, FBDD
may be used more extensively. As the number of targets and protein families
grows, we might be able to determine whether specific binding pocket
characteristics are necessary for effective FBDD.
Prospects for the future of FBDD

• Drug leads that come from fragment-based drug design are more likely to be
effective. It is anticipated that the fragment strategy would enhance lead compound
development quality and productivity in pharmaceutical R&D over the next ten
years. The fragmented approach of the future will progress in two directions: first,
it will expand and combine fragments into libraries for functional screening, and
second, it will break down HTS hits into component fragments for individual
optimization. Many of the medications and molecules that FBDD found made it to
clinical trials.
CONCLUSION

• Drug discovery initiatives should use fragment-based drug design. Fragment-based

drug design can be applied to a variety of targets, and the fragment screening hit
rate can also be used to evaluate the target's drug ability. This information can then
be used to direct HTS efforts and provide evidence for a project's approval or
rejection. Furthermore, creating strong binders of a protein without enzymatic
activity is a great use for FBDD. FBDD has emerged as a credible substitute for
large compound library high throughput screens.
References:
• Pharma.Tips. (2025, April 1). Fragment-based drug design (FBDD). Pharma.Tips.
https://pharma.tips/fragment-based-drug-design-fbdd/
• Dr. Alika Farhan. (2023). Fragment-based drug design (FBDD). Journal of Medicinal
and Organic Chemistry, 6(3), 58–60. https://doi.org/10.37532/jmoc.2023.6(3).58-60
• Pradnya Prashant Shinde, Monika Gopal Shinde. (2024). Fragment Based Drug
Design: A Review. International Journal of Pharmaceutical Sciences, Volume 02 |
Issue 07 | Article Id IJPS/240206196
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