Rascore

Rascore maps the conformational landscape of human RAS isoforms KRAS, NRAS, and HRAS using structural analysis of 721 Protein Data Bank (PDB) entries to support interpretation of mutation and inhibitor effects.

Key Features:

• Expanded Conformational Classification: Classifies catalytic switch regions SW1 and SW2 into three SW1 conformations and nine SW2 conformations linked to nucleotide states (GTP-bound, nucleotide-free, GDP-bound) and specific protein or inhibitor interactions.
• Density-Based Machine Learning Clustering: Applies a density-based machine learning algorithm to cluster the spatial positions of residues Y32 in SW1 and Y71 in SW2, identifying additional conformational subsets including previously undescribed ones.
• Detailed Analysis of Mutations and Inhibitors: Analyzes the structural impact of common RAS mutations such as G12D and G12V and characterizes the chemistries of inhibitors that bind to distinct druggable conformations.
• Comprehensive Structural Catalog: Analyzes 721 human RAS structures from the PDB, including 206 RAS-protein cocomplexes, 190 inhibitor-bound structures, and 325 unbound structures, to serve as a structural catalog for therapeutic targeting.

Scientific Applications:

• Facilitate Drug Discovery: Identifies druggable conformations and elucidates inhibitor-binding modes to inform development of targeted therapies for cancers driven by RAS mutations.
• Understand Mutation Impacts: Clarifies how specific mutations such as G12D and G12V alter RAS structure and function to support mutation-specific therapeutic strategies.
• Guide Therapeutic Targeting: Highlights potential binding sites and conformations amenable to inhibition to support rational drug design against RAS isoforms.

Methodology:

Performs density-based machine learning clustering of spatial positions of Y32 and Y71, classifies SW1 and SW2 into three and nine conformations respectively linked to GTP-bound, nucleotide-free, and GDP-bound states, and analyzes 721 human RAS structures from the Protein Data Bank (206 RAS-protein cocomplexes, 190 inhibitor-bound, 325 unbound).