The natural productome

Abstract

Natural products have inspired many highly impactful human medicines, crop protectants, food preservatives, and biological probes. They also make the world a more wonderful place to see, smell, taste, and feel, by serving as many of the most popular colorants, perfumes, seasonings, and lotions (Fig. 1). Having the capacities to disrupt or promote protein–protein interactions (1), allosterically modify protein activities (2), and even autonomously perform protein-like functions (3), natural products continue to inspire the medicines of tomorrow. With such an extensive track record of contributions to society, the question of how much untapped potential natural products possess is an important one. Pye et al. (4) report in PNAS a quantitative analysis of the structural novelty of most of the microbial and marine-derived natural products discovered over the past 70 y. Their findings support what may seem at first glance to be paradoxical conclusions: natural product chemical space is largely bounded, and the opportunity for future discovery in this arena is substantial (Fig. 1). Fig. 1. Natural products have already made extensive contributions to society. The finding that the chemical space they occupy is largely bounded paradoxically reveals substantial opportunity for future impact. Previous support for the notion that natural product chemical space is limited can be drawn from various angles. It has been theorized that because many natural products have coevolved with protein-binding partners, the boundedness of protein fold-space and the small number of structurally distinct ligand-binding pockets (5) has reciprocally imparted limitations on the structural space they occupy (6). Analogous to the assembly and folding of proteins, even the most topologically complex natural products are typically derived from modular assembly of just a few building blocks and intramolecular cyclizations of the resulting linear structures. These processes are fundamentally bounded by the laws of physical chemistry (5). The tailoring of these … [↵][1]1To whom correspondence should be addressed. Email: mdburke{at}illinois.edu. [1]: #xref-corresp-1-1