Catalytic bioorthonics: design of programmable heterocyclic copper machines for selective therapy.

Key achievement: We have discovered a new class of catalytic therapeutics, the action of which is based not on inhibition, but on the introduction of an artificial catalytic cycle activated by the pathological environment itself (pH, H₂O₂) into the pathological focus. 1. What has been done (experimental breakthrough): A causal relationship has been established between the structure of the copper complex and the opposite biological effects in vivo (from inflammation relief to its provocation). A new type of H₂O₂ catalysis by hybrid heterocyclic complexes has been discovered, where the active site mimics porphyrin, but is built from available "parts" (pyridine/imidazole + pyrrole). The mechanism of selectivity has been deciphered: Catalysts remain inert normally, but go into an overactive state only in the simultaneous presence of two markers of pathology — acidosis and oxidative stress (H₂O₂). Direct analytical evidence of the catalyst in vivo was obtained: conversion of tryptophan to alanine at the site of application. 2. Explained (Theoretical Foundation – DFT): A simple rule of activity is derived: The catalytic function occurs only when aromatic heterocycles (pyridine/imidazole) are combined with pyrrole heterocycles in the coordination sphere. A universal descriptor has been discovered: The effective charge on copper (qCu) is directly correlated with catalytic aggressiveness. The more negative it is, the more powerful the radical catalysis. The principle of the "charged spring" is revealed: In the architecture of the "histidine bracket", complexes are able to accumulate energy and release it when the bracket is triggered, which explains their "explosive" action. 3. Why does it change the paradigm (significance): From inhibition to catalytic sabotage: Instead of blocking a single protein, we propose a total metabolic sabotage act—the irreversible diversion of a key substrate (tryptophan) from the NAD⁺ pathway that is vital to the tumor. Principle of non-resistance: A pathogen cannot develop resistance to direct catalytic oxidation of its critical structures, paving the way for a new generation of antimicrobial and antifungal agents. Rational Design Methodology: Established rules (combination of heterocycles, qCu) and a tool (DFT calculation of qCu) allow the virtual design of catalysts with programmable aggressiveness, from selective correctors to potent cytotoxic agents. The work is a closed cycle: from an unexpected in vivo effect through a complete in silico explanation to the creation of new, more potent agents and the formulation of a general strategy of "catalytic pharmacology". The material includes comprehensive experimental data (in vivo tests, analytical chemistry) and fundamental theoretical justification (a full set of DFT calculations with key parameters), which makes it unique in its breadth of coverage and practical orientation.