ChemGPS-NP: Tuned for Navigation in Biologically Relevant Chemical Space

Division of Pharmacognosy, Department of Medicinal Chemistry, BMC, Uppsala University, Box 574, S-751 23 Uppsala, Sweden.
Journal of Natural Products (Impact Factor: 3.8). 06/2007; 70(5):789-94. DOI: 10.1021/np070002y
Source: PubMed


Natural compounds are evolutionary selected and prevalidated by Nature, displaying a unique chemical diversity and a corresponding diversity of biological activities. These features make them highly interesting for studies of chemical biology, and in the pharmaceutical industry for development of new leads. Of utmost importance, for the discovery of new biologically active compounds, is the identification and charting of the corresponding biologically relevant chemical space. The primary key to this is the coverage of the natural products' chemical space. Here we introduce ChemGPS-NP, a new tool tuned for handling the chemical diversity encountered in natural products research, in contrast to previous tools focused on the much more restricted drug-like chemical space. The aim is to provide a framework for making compound classification and comparison more efficient and stringent, to identify volumes of chemical space related to particular biological activities, and to track changes in chemical properties due to, for example, evolutionary traits and modifications in biosynthesis. Physical-chemical properties not directly discernible from structural data can be discovered, making selection more efficient and increasing the probability of hit generation when screening natural compounds and analogues.

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    • "This step is essential because of the well-recognized disparity between commercial fragment libraries and natural products—commercial fragments have a structural makeup that is largely biased toward readily available small, flat, heterocyclic molecules, whereas natural products have a prevalence of stereogenic centers and even include reactive functional groups.[3b, 10] In the first step of the method, a set of known ligands of both the protein of interest (where available) as well as other related proteins is compiled. Subsequently, a fragment library is assembled that samples the substructural chemical space present in the ligands and is hence expected to increase fragment hit rates. "
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    • "Is it not time to, at least for a while, study those already well-defined chemical structures? Furthermore, the selection of organisms for collection and further studies could in much higher degree be based on prediction models, for example, combining phylogeny with bioinformatic data (Larsson et al., 2007). Also important for a sustainable use of natural products is the increased knowledge emerging about the real producer of specific secondary metabolites found in plants and animals. "
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