Natural products protein interactions

The nature of plants having secondary metabolites as defensive agents greatly increases the expectation that there will be interactions with other botanical products and drugs. If well-established traditional botanical products are used according to directions, they are likely a low risk. Risk increases when botanical products are combined with conventional drug therapies and lies in the possibility of unknown natural product-drug interactions. Other risks include product deviation due to misidentification of species, the lack of standardization, or adulteration. Most of the interactions have been reported with cytochrome P-450 (CYP) 3A4, but there are interactions with other metabolism enzymes and transport proteins. 

The term biology-oriented synthesis (BIOS) [45] has been used to describe the design of compound libraries based on biologically relevant chemical space [46]. The areas in protein structures that participate in productive protein-ligand interactions have been, for the most part, already defined by natural products and drugs. Thus libraries inspired by natural products and other bioactive molecules are expected to have a higher probability of biologically activity than randomly synthesized molecules [47,48]. 

The cause of the cell cycle specificity of the bisindole alkaloids may be associated with the ability of these compounds to interact with the protein tubulin and thereby inhibit the polymerization (and depolymerization) of microtubules (16,17). In this respect the cellular pharmacology of vinca alkaloids is similar to that of other cytotoxic natural products such as colchicine or podophyllotoxin. On closer inspection, however, Wilson determined that the specific binding site on tubulin occupied by vinblastine or vincristine is chemically distinct from the site occupied by the other natural products (18). Subsequent experiments have determined that the maytansinoids, a class of ansa-macrocycles structurally distinct from the bisindoles, may bind to tubulin at an adjacent (or overlapping) site (19). A partial correlation of the antimitotic activity of these compounds with their tubulin binding properties has been made, but discrepancies in cellular uptake probably preclude any quantitative relationship of these effects (20). 

Many natural products contain heterocyclic motifs, which afford addihonal recognition elements for interaction with nucleotide and protein targets. Within a given molecule, heterocycles can occur as single, tandem and multiple moieties within a given molecule (Figure 7.2). 

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