C-H functionalisation tolerant to polar groups could transform fragment-based drug discovery (FBDD)

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Drug Discovery

Background:

• Fragment-based drug discovery (F2L) is a key strategy for identifying novel drug candidates.
• Analysis of existing F2L examples provides insights into successful fragment-protein interactions and synthetic elaboration.
• Understanding common binding motifs and synthetic vectors is crucial for optimizing F2L pipelines.

Purpose of the Study:

• To analyze X-ray structural data from 131 fragment-to-lead examples (2015-2019).
• To identify prevalent polar functional groups involved in fragment-protein binding.
• To determine common synthetic growth vectors during fragment elaboration into leads.

Main Methods:

• Analysis of published X-ray structural data for 131 fragment-to-lead cases.
• Identification and quantification of polar functional groups mediating fragment-protein interactions.
• Assessment of synthetic routes and bond formation during fragment-to-lead conversion.

Main Results:

• The most common polar functional groups in fragment-protein binding are N-H donors (35%), aromatic nitrogen acceptors (23%), and carbonyl oxygen acceptors (22%).
• In approximately 80% of cases, synthetic elaboration originates from aromatic or aliphatic carbon atoms on the fragment.
• Over 50% of newly formed bonds during lead generation are carbon-carbon bonds, highlighting carbocentric growth.

Conclusions:

• Carbocentric growth vectors are critical in fragment elaboration.
• Development of C-H functionalization methods that tolerate polar groups could significantly advance fragment-based drug discovery (F2L).
• The study provides a valuable dataset and interactive resource for the drug discovery community.