Synergistic Machine Learning Accelerated Discovery of Nanoporous Inorganic Crystals as Non-Absorbable Oral Drugs.

Abstract

Machine learning (ML) has taken drug discovery to new heights, where effective ML training requires vast quantities of high-quality experimental data as input. Non-absorbable oral drugs (NODs) have unique safety advantage for chronic diseases due to their zero systemic exposure, but their empirical discovery is still time-consuming and costly. Here, a synergistic ML method, integrating small data-driven multi-layer unsupervised learning, in silico quantum-mechanical computations, and minimal wet-lab experiments is devised to identify the finest NODs from massive inorganic materials to achieve multi-objective function (high selectivity, large capacity, and stability). Based on this method, a NH₄-form nanoporous zeolite with merlinoite (MER) framework (NH₄-MER) is discovered for the treatment of hyperkalemia. In three different animal models, NH₄-MER shows a superior safety and efficacy profile in reducing blood K⁺ without Na⁺ release, which is an unmet clinical need in chronic kidney disease and Gordon's syndrome. This work provides a synergistic ML method to accelerate the discovery of NODs and other shape-selective materials.