Everyone doing biochemistry will at some point realize that by extracting certain components from a cell or even tissue does not mean that you can really understand how the whole system works. All the molecular entities are somehow organized in space and time and interact with each other, integrating signals and producing output. By reducing the system to something that is easily handled in the lab (a pure protein fraction, a single molecule, etc.) we can at least understand part of it. Thinking about small signalling molecules in the cell and how they may have evolved brings up some intriguing questions. How does everything fit together and how on earth were all these receptors and their endogenous ligands generated by nature to produce such an array of physiological functions? What a challenge to thermodynamics!
It seems feasible that nature produces pools of molecules and by chance some of them interact and by chance some of them produce a function and by chance this will somhow provide a means of fitness and thus it will be selected for. How could such an incredible number of molecules have been generated to provide the basis for molecular interactions that lead to physiology? To quote the Russian Orthodox Christian Theodosius Dobzhansky: nothing in biology makes sense if not in the light of evolution. Even though I don't have an answer I think it is likely that there are many privildeged structures that are more probable to interact than others. Such structures are seen in proteins, but also in small organic molecules. Natural products, which are produced by all life forms (why exactly is not understood), could represent an organism's pool (molecular portfolio) for potential chemical interactions (e.g. with the environment or within a tissue).
During the early history of medicine, people simply took extracts of plants containing natural products and applied them somehow. In many cases, they felt that these extracts had some impact on their body, e.g. anti-inflammatory or psychomodulatory. In many cases the properties attributed to plants were medicinal. Even today many people apply botanical drugs as mixtures and often it is not clear whether the effect is due to a single substance of the whole mixture. What happens when humans take the molecular portfolio of plants (generated by evolution) and ingest it? In a recent review "Gertsch, 2011" I have addressed the complex issues involved in botanical drugs and how nature makes use of synergies and how the often reductionist view of drug action for complex diseases may be inspired by nature.
Botanical Drugs, Synergy, and Network Pharmacology: Forth and Back to Intelligent Mixtures
For centuries the science of pharmacognosy has dominated rational drug development until it was gradually substituted by target-based drug discovery in the last fifty years. Pharmacognosy stems from the different systems of traditional herbal medicine and its "reverse pharmacology" approach has led to the discovery of numerous pharmacologically active molecules and drug leads for humankind. But do botanical drugs also provide effective mixtures? Nature has evolved distinct strategies to modulate biological processes, either by selectively targeting biological macromolecules or by creating molecular promiscuity or polypharmacology (one molecule binds to different targets). Widely claimed to be superior over monosubstances, mixtures of bioactive compounds in botanical drugs allegedly exert synergistic therapeutic effects. Despite evolutionary clues to molecular synergism in nature, sound experimental data are still widely lacking to support this assumption. In this short review, the emerging concept of network pharmacology is highlighted, and the importance of studying ligand-target networks for botanical drugs is emphasized. Furthermore, problems associated with studying mixtures of molecules with distinctly different pharmacodynamic properties are addressed. It is concluded that a better understanding of the polypharmacology and potential network pharmacology of botanical drugs is fundamental in the ongoing rationalization of phytotherapy.© Georg Thieme Verlag KG Stuttgart · New York.