Defining and navigating macrocycle chemical space.

Area of Science:

• Medicinal Chemistry and Chemical Biology
• Drug Discovery and Development
• Computational Chemistry

Background:

• Macrocyclic compounds (MCs) are increasingly recognized for their potential in inhibiting difficult drug targets.
• Understanding the structural and physicochemical properties influencing MC bioactivity is crucial for drug design.

Purpose of the Study:

• To analyze the structure-property relationships of macrocyclic compounds, differentiating between oral and non-oral drugs.
• To identify key molecular features that enable oral bioavailability in macrocyclic drug candidates.
• To guide the design of novel synthetic macrocyclic compounds with improved oral bioavailability.

Main Methods:

• Principal Component Analysis (PCA) was employed to map macrocyclic drugs, clinical candidates, and synthetic compounds in structure-property space.
• Analysis focused on identifying distinct regions associated with oral versus non-oral macrocyclic drugs.
• Key physicochemical and structural properties relevant to oral bioavailability were identified.

Main Results:

• Oral macrocyclic drugs occupy specific, well-defined regions within the analyzed structure-property space.
• These regions are distinct from those occupied by non-oral macrocyclic drugs.
• Commercially available synthetic macrocycles do not effectively sample the chemical space associated with oral macrocyclic drugs.

Conclusions:

• Identification of 13 critical properties for designing synthetic macrocycles that overlap with the desirable regions of oral MC drugs.
• Enhanced understanding of molecular features correlating with bioactivity and oral bioavailability in macrocyclic compounds.
• Provides a framework for synthetic chemists to evaluate macrocycle designs and explore underexplored regions of macrocycle chemical space.