Intelligent design and construction of novel APN-based theranostic probe driven by advanced computational methods

Multifunctional molecules with both optical signal and pharmacological activity play an important role in drug development, disease diagnosis, and basic theoretical research. Aminopeptidase N (APN), as a representative tumor biomarker with anti-tumor potential, still lacks a high-precision theranostic probe specifically targeting it. In this study, a novel quaternity design strategy for APN theranostic probe was developed. This proposed strategy utilizes advanced machine learning and molecular dynamics simulations, and cleverly employs the strategy of conformation-induced fluorescence recovery to achieve multi -objective optimization and integration of functional fragments. Through this strategy, a unique Off-On theranostic probe, ABTP-DPTB, was ingeniously constructed to light up APN through fluorescence restoration, relying on conformation-induced effects and solvent restriction. Differ from the common diagnostic probes, the intelligent design with non-substrated linkage makes ABTP-DPTB for long-term in-situ imag-ing. The fabricated probe was used for detecting and inhibiting APN in various environments, with a better in vitro inhibitory than golden-standard drug bestatin.(c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

Multifunctional molecules with both optical signal and pharmacological activity are important in drug development, disease diagnosis, and theoretical research. In this study, a novel design strategy for a theranostic probe targeting a representative tumor biomarker, aminopeptidase N (APN), was developed using machine learning and molecular dynamics simulations. The resulting probe, ABTP-DPTB, utilizes conformation-induced fluorescence recovery to detect and inhibit APN.