Navigating condensate micropolarity to enhance small-molecule drug targeting

Area of Science:

• Biochemistry
• Molecular Pharmacology
• Drug Discovery

Background:

• Pharmaceutical targets often localize within biomolecular condensates.
• Condensate microenvironments can alter drug distribution and target engagement.
• Current drug design principles do not fully account for condensate influences.

Purpose of the Study:

• To investigate how condensate microenvironments impact drug-targeting efficiency.
• To establish new drug design strategies for phase-separated protein targets.
• To understand the role of hydrophobicity in drug-condensate interactions.

Main Methods:

• Systematic investigation of condensate properties and drug interactions.
• Analysis of the L1000 dataset for correlations between inhibitor properties and targeting efficiency.
• Development of random forest models to predict drug targeting efficiency.
• In cellulo experiments using estrogen receptor 1 (ESR1) condensates.

Main Results:

• Condensates exhibit heterogeneity; nonpolar-enriched condensates are more hydrophobic.
• Hydrophobic drugs are preferentially housed in hydrophobic condensates.
• A strong positive correlation exists between inhibitor hydrophobicity and targeting efficiency for phase-separated proteins like ESR1.
• Hydrophobicity is a key determinant in predicting inhibitor targeting efficiency.
• Both binding affinity and inhibitor hydrophobicity significantly contribute to potency in ESR1 condensates.

Conclusions:

• Condensate micropolarity is a critical factor for designing drugs targeting phase-separated proteins.
• Incorporating condensate properties into drug design can lead to optimized target engagement.
• This study proposes a novel drug design principle for phase-separated targets.