In Silico Hit-to-Lead Optimization of De Novo Macrocyclic Peptidomimetics Targeting the β-Catenin/TCF4 Interface: A Rigid-Body Heuristic Approach

β-catenin/TCF4 interaction: One of the most sought-after targets in oncology — implicated in colorectal cancer, Gardner syndrome, and triple-negative breast cancer — yet no approved drug exists that directly disrupts it. This paper reports the first hit-to-lead campaign for a structurally unprecedented class of 15-membered macrocyclic scaffolds discovered de novo by the author's GeoSol-αα computational pipeline. Using exhaustive rigid-body sampling of over 1.3 million spatial poses per candidate, the work identifies and characterizes two lead derivatives. Demonstrates that a single-atom isosteric substitution preserves perfect pharmacophoric geometry while improving drug-like properties, and exposes a higher-scoring candidate as a computational false positive. All three structures are confirmed as New Chemical Entities with no prior record in global patent and chemical databases.