**6. Natural products help**

Natural products are mainly derived from plants as the result of coevolution between organisms and environment. For this reason, they are used for centuries in popular and traditional medicines, as well as often as spices and insecticides. Unlike modern pharmacology and drug development based on single chemical entity, natural product preparations are multi-ingredient, derived from the historical references and empirical experiences. A single herbal drug contains at least hundred of compounds making a complex matrix, named phytocomplex in which not the single active constituent is considered the only responsible for the overall efficacy. The phytocomplex utilization is not a philosophy because many data afford the validity of this approach and others can be obtained using the modern pharmaco‐ logical devices.

The study produced in 2010 by MIT and the Broad Institute of Harvard University (US) is a clear step in the direction of a scientific validation of natural products [39]. The argument strictly relates to the past and future role of natural products and the endless debate about their efficacy, often resulting into a fighting contrast between natural products supporters vs. synthetic drugs defenders. The key argument was to understand what is going on between the two main levels of the metabolism, involving the functional connection between genes and genes products and between targets and genes. The MIT researchers decided to commit the argument to the neutral judgment of artificial intelligence. The computational work was based on the comparison of cumulative connectivity distribution of small molecules, natural or synthetic, grouped according to connectivity associated with the target, assuming that proteins form biological networks. The result is simple: natural products target the proteins with a high number of protein–protein functional interactions (higher network connectivity), whereas the synthetic ones act on limited protein network: "We observe that approved drug targets that are not also natural product target exhibit a connection distribution much closer to the case for human disease genes that natural product targets, which remain the most highly connected targets."

Natural products tend to target proteins more essential and general to an organism than other groups of small-molecule targets, like those related to disease genes. They therefore work as a nonspecific basic defense against predators or pathogens acting on more highly connected proteins, interrupting essential protein activity of the environmental competitor or invader. However, natural products are not only defense and toxic substances. On the contrary, the story of plant evolution and the experience evidence the progressive production of positive substances produced in favor of a collaboration with the animals present in the same habitat. They may be tailored for a positive or negative influence in physiologic activities and basic metabolism. These argumentations are in favor of the potential use of natural products as insecticides.
