Distinct biological network properties between the targets of natural products and disease genes

Abstract

We show that natural products target proteins with a high number of protein-protein functional interactions (high biological network connectivity) and that these protein targets have higher network connectivity than disease genes. This feature may facilitate disruption of essential biological pathways, resulting in competitor death. This result also suggests that additional sources of small molecules will be required to discover drugs targeting the root causes of human disease in the future.

Figure 1

(a) Connectivity summary of different protein groups: all human proteins in STRING database (blue: n = 8799; median = 5; mean = 11.7), disease-associated proteins (green: n = 2681; median = 6; mean = 14.0), natural product targets (red: n = 946; median = 11; mean = 22.5). (b) Cumulative connectivity distributions.

Figure 2

(a) Comparison of cumulative connectivity distributions between targets of 76 manually selected natural products (gold: n = 38; median = 32.5; mean = 48.5) and the database of natural products (red; same as Figure 1b). (b) Representative natural products obtained from literature review, grouped according to connectivity associated with the target.

Figure 3

Comparison of cumulative connectivity distributions between other small-molecule targets from ChEMBL(15) (gold: n = 729; median = 8; mean = 17.4), natural product targets (red; same as Figure 1b), and human disease genes (green; same as Figure 1b).

Figure 4

Comparison of cumulative connectivity distributions between approved drug targets from DrugBank(16) (gold: n = 731; median = 7; mean = 14.9), natural product targets (red; same as Figure 1b), and human disease genes (green; same as Figure 1b).