Skeleton innovation versus structural diversification in terpenoid discovery: chemoinformatic insights from TeroKit

Abstract

Covering: up to the end of 2025

Terpenoids, as one of the largest classes of natural products, derive their vast structural diversity from a combination of complex cyclic skeletons and extensive post-modifications. Although new terpenoids continue to be discovered, it has remained unclear whether contemporary research is primarily in a phase of exploring novel carbon skeletons or exploiting known ones through elaboration. Our systematic chemoinformatic investigation reveals that terpenoid discovery in the past six years has been overwhelmingly dominated by the exploitation of known skeletons through diverse modifications. This trend is largely driven by the current, activity-guided discovery paradigm, which prioritizes compounds with drug-like properties and immediately assayable bioactivity, thereby focusing effort on the elaboration of accessible chemical space. This quantitative profiling provides a clear framework for understanding the present trajectory of the field and underscores the need to strategically rebalance exploration and exploitation in future research, guiding efforts toward uncovering truly unprecedented and biologically relevant terpenoid architectures.