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NMR-Based Fragment Screening in a Minimum Sample but Maximum Automation Mode
Published on: June 4, 2021
Fragment-based drug design: how big is too big?
1Pharmaceutical Discovery Division, Abbott Laboratories, R46Y, AP-10, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. philip.hajduk@abbott.com
Journal of Medicinal Chemistry
|November 28, 2006
Summary
This study reveals a linear relationship between molecular weight and binding affinity in fragment leads during drug design. These findings help define optimal size and potency for effective fragment-based drug design.
Area of Science:
- Medicinal Chemistry
- Computational Drug Design
Background:
- Physicochemical properties of fragment leads are crucial in drug design.
- The impact of fragment lead potency on optimization has been less explored.
Purpose of the Study:
- To investigate the relationship between molecular weight, size, and binding affinity of fragment leads.
- To establish quantitative guidelines for selecting and optimizing fragment leads in drug discovery.
Main Methods:
- Retrospective analysis of 18 highly optimized inhibitors.
- Systematic deconstruction of compounds to identify minimal binding elements.
- Analysis of potency changes during lead size reduction.
Main Results:
- A nearly linear correlation was observed between molecular weight and binding affinity across various sizes.
- The data suggest a direct relationship between fragment size and inhibitory potency.
- Prediction maps were constructed to aid in lead identification and optimization assessments.
Conclusions:
- Molecular weight and binding affinity are closely linked in fragment-based drug design.
- Defined limits for ideal fragment lead size and potency can be established.
- This research provides a quantitative framework for optimizing fragment leads.
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