Drug Design: Do Not Forget the Supramolecular Factor.

Area of Science:

• Medicinal Chemistry
• Supramolecular Chemistry
• Antimicrobial Drug Discovery

Background:

• Emergence of drug-resistant fungi and bacteria presents a significant challenge in medicinal chemistry.
• Current drug discovery approaches often overlook the supramolecular factor, which influences drug selectivity.
• Aggregated forms of drug candidates can exhibit lower selectivity compared to their monomeric counterparts.

Purpose of the Study:

• To investigate the role of the supramolecular factor in drug selectivity.
• To test the hypothesis that monomers of antifungal agents are more selective than their aggregates.
• To provide a rationale for incorporating supramolecular considerations into drug design and testing.

Main Methods:

• Fundamental studies using simple model systems to understand supramolecular behavior.
• Reasoning based on theoretical selectivity differences between monomeric and aggregated drug forms.
• Experimental validation using derivatives of the antifungal agent amphotericin B.

Main Results:

• Confirmed that monomeric forms of amphotericin B derivatives exhibit significantly greater selectivity than their aggregated forms.
• Demonstrated that supramolecular aggregation state directly impacts the selectivity of drug candidates.
• Provided empirical evidence supporting the hypothesis regarding monomer vs. aggregate selectivity.

Conclusions:

• The supramolecular factor is critical for achieving selective cell destruction by drug candidates.
• Monomeric forms of drugs, like amphotericin B, offer enhanced selectivity against targeted cells.
• Future drug design and testing should systematically consider the supramolecular state of drug molecules.