Cell wall target fragment discovery using a low-cost, minimal fragment library

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Drug Discovery

Background:

• Fragment-based inhibitor design is a key strategy in drug discovery.
• Current fragment libraries face challenges with solubility, reactivity, cost, and accessibility.
• There is a need for cost-effective and readily available fragment sets for screening.

Purpose of the Study:

• To design and validate a low-cost, minimal fragment library (LoCoFrag100) for crystallographic screening.
• To assess the library's utility in identifying potential inhibitors for microbial enzymes.
• To provide an accessible tool for evaluating target ligandability in any laboratory setting.

Main Methods:

• Designed LoCoFrag100 with an average cLogP of 0.03 and cost of £20/g.
• Formatted the library in a 10x10 matrix to minimize Tanimoto similarity within 20 cocktails.
• Screened the library against three distinct enzymes involved in microbial cell wall synthesis using crystallography.

Main Results:

• Achieved hit rates of 1-6% across the three tested enzymes.
• Identified three fragments that show potential for further inhibitor development.
• Demonstrated the library's effectiveness in rapidly assessing target ligandability.

Conclusions:

• LoCoFrag100 is a practical and affordable fragment library for crystallographic screening.
• The library facilitates rapid assessment of target ligandability, aiding in early-stage drug discovery.
• LoCoFrag100 provides valuable data for prioritizing targets for subsequent inhibitor design and optimization.