“Marine Rule”: discovery of marine natural small molecule drug leads in China in the past decade

Abstract

This review systematically analyzes 186 valid data points derived from 157 distinct marine natural small-molecule drug leads discovered in China in the past decade (2015-2024). These compounds have all undergone phenotypic and target studies, and certain "structure-activity-target" relationships have been established, revealing the recent progress in the basic research of marine drug discovery in China. Therapeutically, antitumor agents dominated (50.0%), while emerging candidates for Alzheimer’s disease (3.8%) and osteoporosis (5.4%) demonstrated the multi-target potential of marine chemistry. Ecologically, marine fungi (45.2%) and mangrove symbionts (11.8%) have emerged as prolific sources. Strikingly, 38.2% of the compounds exceeded Lipinski’s 500 Da threshold, with higher-molecular-weight agents leveraging macrocyclic architectures (e.g., polyketide-alkaloid hybrids) to enhance bioactivity. These findings challenge traditional drug-likeness criteria and propose a “Marine Rule” framework that prioritizes conformational rigidity, ecosystem-driven scaffold optimization, and the repurposing of defense molecules. This review provides critical insights into China’s evolving leadership in marine natural product research and offers strategic guidance for future innovations in the discovery of small molecule leads.

Keywords

Marine drug / Natural products / Lead compounds / Pharmacological activities / Marine rule

Funding

This work was supported by the Special Project for Marine Economic Development of the Department of Natural Resources of Guangdong Province (No. GDNRC[2024]25).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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