RESISTOR

RESISTOR predicts potential drug-resistant protein mutations to identify sequence and structural variants that diminish inhibitor efficacy and inform therapeutic design.

Key Features:

• Structure- and Sequence-Based Criteria: RESISTOR employs both structural and sequence-based approaches to identify mutations that could confer resistance to specific inhibitors.
• Integration with OSPREY: RESISTOR is implemented within the OSPREY computational protein design framework.
• Evolutionary Simulation: RESISTOR simulates protein evolutionary responses under selective pressure from therapeutic agents using molecular-level analyses.
• Identification of Mutations Affecting Drug Efficacy: RESISTOR identifies mutations predicted to diminish the efficacy of drugs, including ERK1/2 inhibitors such as SCH779284.
• Structural and Sequence Analysis of Targets: RESISTOR analyzes structural and sequence characteristics of target proteins to prioritize resistance-conferring substitutions.

Scientific Applications:

• Predicting Resistance in Melanoma: RESISTOR was used to predict resistance mutations in ERK2 in melanoma that may reduce efficacy of the ERK1/2 inhibitor SCH779284 (Guerin et al., PMID: 37115667).
• Therapeutic Design: RESISTOR's predictions can be used to anticipate resistance mechanisms and guide the design of inhibitors with improved robustness to evolutionary changes.

Methodology:

Uses structural- and sequence-based analyses to evaluate target proteins and simulates evolutionary responses to therapeutic selective pressure; implemented within the OSPREY computational protein design framework.