Fragment-Based Drug Design (FBDD)

Method

Fragment-Based Drug Design (FBDD) is a method in drug discovery where chemical fragments up to 17 heavy atoms are used as starting points for developing new drugs. These fragments can typically bind more easily to different regions of a target protein. The fragments are then optimized through a series of iterations to improve their binding affinity, specificity, and drug-like properties.

Importance in Computational Drug Discovery:

Efficiency: FBDD allows for the exploration of a larger chemical space with fewer compounds compared to traditional high-throughput screening. This makes it more efficient and cost-effective.
Novelty: Fragments can bind to unique and novel sites on target proteins that might be missed by larger molecules, providing opportunities to discover new binding sites and/or ways to modulate function.
Optimization: Fragments provide a modular approach to drug design, allowing for systematic optimization of binding affinity and specificity.
Structural Insights: Fragments typically bind with low affinity and require techniques sensitive enough to measure binding events. As such, FBDD often involves the use of X-ray crystallography and NMR spectroscopy, providing detailed insights into the binding interactions between fragments and target proteins.
Scaffold Hopping: Fragments can serve as starting points for scaffold hopping, a technique used to develop new compounds with similar biological activity but different core structures.

Key Tools

Schrödinger Suite:
- Tools like Glide for docking, Maestro for visualization, and Prime for protein structure prediction and refinement, which are essential for fragment-based approaches.
OpenEye Scientific Software:
- Provides tools like FRED for docking, ROCS for shape-based screening, and QUACPAC for charge assignment, useful in FBDD.
DeepOrigin Tools:
- Use Balto to:
  1. Retrieve or import a fragment libraries.
  2. Filter and analyze fragments for desirable properties.
  3. Virtually screen fragments against a protein binding site.
  4. Analyze and prioritize fragment hits for further optimization.
XChemExplorer:
- A tool specifically designed for managing and analyzing fragment-based screening data obtained from X-ray crystallography experiments.
Cresset Software:
- Includes tools like Forge and Spark for molecular design and optimization, focusing on fragment-based approaches.

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Literature

Fragment-based Drug Discovery Strategy and its Application to the Design of SARS-CoV-2 Main Protease Inhibitor

Publication Date: 2024-03-25
DOI: 10.2174/0109298673294251240229070740
Summary: This paper discusses the application of FBDD in developing inhibitors for SARS-CoV-2 main protease, highlighting its effectiveness in drug design.

Review of the impact of fragment-based drug design on PROTAC degrader discovery

Publication Date: 2024-01-01
DOI: 10.1016/j.trac.2024.117539
Summary: Reviews the impact of FBDD on the discovery of PROTAC degraders, emphasizing its role in enhancing drug discovery processes.

Discovery of novel potent drugs for influenza by inhibiting the vital function of neuraminidase via fragment-based drug design (FBDD) and molecular dynamics simulation strategies

Publication Date: 2023-08-28
DOI: 10.1080/07391102.2023.2251065
Summary: Describes the use of FBDD and molecular dynamics simulations to generate new neuraminidase inhibitors for influenza, showing promising results in stability and binding affinity.

Discovery of inhibitors against SARS-CoV-2 main protease using fragment-based drug design

Publication Date: 2023-01-12
DOI: 10.1016/j.cbi.2023.110352
Summary: Highlights the discovery of peptide inhibitors for SARS-CoV-2 main protease using FBDD, showcasing their excellent activity and potential as new inhibitors.

Discovery of novel TMPRSS2 inhibitors for COVID-19 using in silico fragment-based drug design, molecular docking, molecular dynamics, and quantum mechanics studies

Publication Date: 2022-02-01
DOI: 10.1016/j.imu.2022.100870
Summary: Discusses the development of TMPRSS2 inhibitors using FBDD and various computational techniques, achieving good binding affinity.

Discovery of the Bruton's Tyrosine Kinase Inhibitor Clinical Candidate TAK-020 (S)-5-(1-((1-Acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one, by Fragment-Based Drug Design

Publication Date: 2021-08-27
DOI: 10.1021/acs.jmedchem.1c01026
Summary: Details the use of FBDD to discover a novel covalent Bruton's tyrosine kinase inhibitor, leading to the clinical candidate TAK-020.

Counting on Fragment Based Drug Design Approach for Drug Discovery

Publication Date: 2019-01-31
DOI: 10.2174/1568026619666181130134250
Summary: Reviews recent advancements and success stories of FBDD in drug discovery, highlighting its efficiency and effectiveness.

Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design

Publication Date: 2017-06-14
DOI: 10.1021/acs.jmedchem.7b00231
Summary: Describes the optimization of IRAK4 inhibitors using FBDD, leading to the clinical candidate PF-06650833 with excellent kinase selectivity.

Development of Computational Approaches with a Fragment-Based Drug Design Strategy: In Silico Hsp90 Inhibitors Discovery

Publication Date: 2021-12-01
DOI: 10.3390/ijms222413226
Summary: Discusses the use of computational approaches and FBDD to design new Hsp90 inhibitors, including a deconstruction and reconstruction process for generating new ligands.

Fragment-based drug design facilitates selective kinase inhibitor discovery

Publication Date: 2021-05-03
DOI: 10.1016/j.tips.2021.04.001
Summary: Introduces the advantages of FBDD in designing selective kinase inhibitors, outlining promising case studies.

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