Recently various attempts have been made to increase the efficacy and precision of chemical libraries used in high-throughput screening (HTS) drug discovery approaches. One such approach is ChemGPS, which provides a defined chemical space for prescreening evaluation of chemical compound properties or virtual dereplication. In the present study, ChemGPS has been applied to a set of natural products shown to exhibit cyclooxygenase-1 and/or -2 (COX-1/2) inhibition. With the purpose of defining chemical properties and linking these to the observed mode of enzyme inhibition, this resulted in two lines of reasoning. On one hand several specific features of these compounds have been identified and discussed. Overall COX inhibition was frequently correlated with the presence of at least one ring in the structure, fragments exhibiting structural rigidity, and a relatively large molecular size. The concept "size" includes several parameters, e.g., molecular volume, weight, and number of bonds. On the other hand, and possibly even more important, was the unexpected finding that the natural products studied to a large extent fell outside the defined ChemGPS chemical space. Therefore, we also propose an expanded space for natural products: ChemGPS-NP.