Bypassing Molecular Dynamics: Ultra-Fast De Novo Generation of Macrocyclic PPI Scaffolds via Rigid-Body SO(3) Deterministic Orientation Sampling and Directed Chemical Evolution

Abstract

Proof of Concept on the β-Catenin/TCF4 Interface in Wnt-Driven Oncogenesis and Gardner Syndrome Protein-protein interactions (PPIs) govern nearly every biological signalling pathway, yet their large, flat contact surfaces have resisted conventional drug design for decades. Existing computational approaches either require prohibitive molecular simulation resources or prior knowledge of a reference inhibitor—barriers that have left many therapeutically important targets inaccessible. This repository presents GeoSol-αα, a two-stage computational pipeline that generates macrocyclic drug scaffolds against PPI surfaces from first principles—without molecular dynamics simulation, without a crystallographic inhibitor reference, and without prior chemical knowledge of the target. The engine couples deterministic rigid-body SO(3) Fibonacci sampling with directed chemical evolution (genetic algorithms). In milliseconds, the pipeline successfully converged on a novel: 15-atom macrocyclic scaffold (1,4-dioxacyclopentadecane) that achieves a thermodynamic optimum with zero desolvation penalty against the β-catenin interface. This repository establishes formal prior art for both the identified chemical entity and the underlying high-throughput methodology.