SAR transfer across different targets.

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Structure-activity relationship (SAR) transfer is crucial in medicinal chemistry but under-investigated.
• Two types exist: target-based SAR (T_SAR) and series-based SAR (S_SAR) transfer.
• S_SAR transfer, where analogs show similar potency changes across multiple targets, has not been systematically explored.

Purpose of the Study:

• To develop and apply a computational approach for detecting S_SAR transfer events.
• To systematically search public compound data for the occurrence of S_SAR transfer.
• To characterize the identified S_SAR transfer series.

Main Methods:

• Devised a computational method to identify S_SAR transfer.
• Systematically searched public domain compound databases.
• Analyzed identified series for structural diversity and potency progression.

Main Results:

• Identified 63 S_SAR transfer series involving two targets and 26 involving three targets.
• No series involving four targets were found.
• Most S_SAR transfers occurred within G protein-coupled receptor (GPCR) subfamilies, not across different target families.

Conclusions:

• S_SAR transfer events are detectable and occur across related targets, primarily within related protein families like GPCRs.
• Identified series exhibit structural diversity but consistent potency progression across targets.
• The findings provide valuable insights into SAR trends for drug discovery and are made publicly available.