Design and Development of Small-Molecule Drugs Targeting Enzymes Utilizing Two-Metal-Ion Catalytic Mechanisms

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Enzymology

Background:

• Many metalloproteins utilize two closely positioned metal ion cofactors (around 3.8 Å apart) for catalysis.
• This two-metal-ion catalytic mechanism (TCM) is crucial for high enzyme efficiency and is found in enzymes vital for human health and pathogens.
• Several TCM enzymes are validated therapeutic targets for various diseases.

Purpose of the Study:

• To review the design and development of small-molecule drugs targeting enzymes with TCMs.
• To highlight successful drug discovery approaches and approved therapeutics.
• To provide insights for future drug discovery efforts targeting TCM enzymes.

Main Methods:

• Review of rational drug design strategies (e.g., nucleoside analogs, prodrugs, structure-based design).
• Exploration of drug repurposing as a therapeutic development strategy.
• Analysis of small-molecule drugs targeting specific TCM enzymes (e.g., RNA-dependent RNA polymerase, HIV-1 integrase).

Main Results:

• Successful application of diverse drug design approaches has led to numerous small-molecule drugs.
• Approved drugs target critical illnesses including hepatitis C, COVID-19, and AIDS.
• Drug repurposing is a key strategy for developing TCM enzyme inhibitors.

Conclusions:

• Small-molecule drugs targeting TCM enzymes have significantly advanced disease treatment.
• Continued research into TCM enzymes and drug design holds promise for future therapeutics.
• This review offers guidance for discovering and developing novel drugs against TCM enzymes.