Assessing drug-likeness--what are we missing?

Area of Science:

• Medicinal Chemistry
• Computational Chemistry

Background:

• Drug-likeness concepts and molecular descriptors like the Rule-of-Five are crucial for optimizing drug properties.
• Current descriptors often represent static molecular features, neglecting dynamic conformational changes.

Purpose of the Study:

• To review current drug-likeness assessment approaches.
• To highlight the limitations of static molecular descriptors.
• To introduce molecular sensitivity as a descriptor for dynamic molecular properties.

Main Methods:

• Review of existing drug-likeness assessment methodologies.
• Analysis of the static nature of traditional molecular descriptors.
• Introduction and conceptualization of molecular property spaces.
• Definition and application of molecular sensitivity as a novel descriptor.

Main Results:

• Traditional drug-likeness descriptors provide a static view of molecules.
• Molecular properties are conformation-dependent, leading to property spaces.
• Molecular sensitivity quantifies the impact of molecular flexibility on properties.
• Molecular sensitivity emerges as a promising descriptor for capturing dynamic molecular information.

Conclusions:

• Static molecular descriptors have inherent limitations in drug design.
• Considering molecular flexibility through property spaces and molecular sensitivity is essential.
• Molecular sensitivity offers a more comprehensive approach to evaluating drug-likeness and optimizing pharmaceutical properties.