Rationalizing the role of SAR tolerance for ligand-based virtual screening

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Ligand-based virtual screening (LBVS) outcomes are sensitive to methodological choices and compound class.
• The influence of structure-activity relationship (SAR) characteristics on LBVS success is less understood.

Purpose of the Study:

• To investigate the hypothesis that prospective LBVS success is influenced by target SAR tolerance, beyond methodological factors.
• To define and analyze SAR tolerance in target proteins and SAR continuity in compound datasets.

Main Methods:

• Generated activity landscape representations for compounds active against 16 diverse target proteins with reported successful LBVS applications.
• Analyzed the SAR environments of newly identified LBVS hits within these activity landscapes.

Main Results:

• Activity landscapes for known active compounds consistently showed multiple regions of local SAR continuity.
• Newly identified LBVS hits predominantly mapped to distinct regions of local SAR continuity.
• A strong correlation was observed between SAR tolerance at the target level and SAR continuity at the ligand level.

Conclusions:

• LBVS success is closely linked to the SAR tolerance of the target protein.
• SAR continuity within compound datasets serves as an indicator of target SAR tolerance and predicts LBVS success.
• Understanding SAR tolerance is crucial for optimizing LBVS strategies in drug discovery.