Guided by evolution: from biology oriented synthesis to pseudo natural products

Area of Science:

• Medicinal Chemistry
• Natural Products Chemistry
• Computational Chemistry

Background:

• Natural products (NPs) are crucial sources of inspiration for designing biologically active compounds and compound libraries.
• Simplifying complex NP structures and understanding their structure-activity relationships are key challenges in drug discovery.
• Existing methods offer valuable frameworks but advancements are needed for efficient NP-inspired library design.

Purpose of the Study:

• To review experimental and in silico approaches for simplifying natural products.
• To guide the design of natural product-based compound libraries.
• To highlight chemical innovations arising from these NP simplification strategies.

Main Methods:

• Review of established methods like Structural Classification of Natural Products (SCONP) and Biology-Oriented Synthesis (BIOS).
• Cheminformatic analysis of the Dictionary of Natural Products (DNP) to identify key NP fragments.
• Combinatorial synthesis strategies for generating pseudo natural products (pseudo NPs).

Main Results:

• Earlier methods (SCONP, BIOS) focused on identifying activity-determining scaffolds for focused library synthesis.
• Recent fragment-based approaches using DNP data have yielded pseudo NPs with novel biological activities.
• All discussed approaches have spurred innovation in synthetic methodologies for rapid assembly of NP-inspired molecules.

Conclusions:

• Diverse experimental and computational strategies effectively simplify natural products for drug discovery.
• Fragment-based approaches offer a powerful route to novel pseudo natural products with unique activities.
• These NP simplification strategies drive synthetic innovation, enabling efficient generation of diverse compound libraries.