Expanding the range of ‘druggable’ targets with natural product-based libraries: an academic perspective

Abstract

Summary of recent advances Existing drugs address a relatively narrow range of biological targets. As a result, libraries of drug-like molecules have proven ineffective against a variety of challenging targets, such as protein–protein interactions, nucleic acid complexes, and antibacterial modalities. In contrast, natural products are known to be effective at modulating such targets, and new libraries are being developed based on underrepresented scaffolds and regions of chemical space associated with natural products. This has led to several recent successes in identifying new chemical probes that address these challenging targets.

The re-emergence of natural products for drug discovery in the genomics era

“…To a certain extent, compound libraries are being designed to mimic more closely the chemical properties of natural products, 10,[13][14][15][16][17] although natural products themselves are generally overlooked.…”

The pharmaceutical industry and natural products: historical status and new trends

“…Chemical synthesis, shifted the focus of drug discovery efforts from nature to the laboratory bench in the late 1980s (Cragg and Newman 2013). Of the 1,135 new drugs approved from 1981 to 2010, 50 % were of NP origin (natural, derivatives and analogues) (Cragg 2007;Schmitt et al 2011;Newman and Cragg 2012) with most of the chemical diversity nearly or completely absent from current small molecule-based screening libraries provided by combichem (Bauer et al 2010). Well known examples include the widely used breast cancer drug, paclitaxel (2) (Taxol Ò ), isolated from the bark of the Pacific Yew, Taxus brevifolia (Dewick 2009) and trabectedin (3) (Yondelis Ò ) isolated from the sea squirt, Ecteinascidia turbinata (currently completing Phase III studies in the US) (Cuevas and Francesch 2009;Cragg and Newman 2013) which provided the first marine anticancer drug to be approved in Europe after cytarabine (4) (1969) (Mayer et al 2010).…”

Diversity-oriented synthesis as a tool for identifying new modulators of mitosis

“…PCA was carried out using the MOE software package 45 . A total of 15 physicochemical properties (Supplementary Table 14) were obtained for established reference sets of 40 top-selling brand-name drugs and 60 diverse natural products and 36 DOS library members 30 . The summary of the contribution of each principal component is shown in Supplementary Table 15 and the component loadings are shown in Supplementary Table 16.…”

“…To computationally assess its structural diversity, we carried out a comparative statistical analysis of a set of molecular descriptors for our DOS library and two reference compound collections, comprising 40 top-selling brand-name drugs and 60 diverse natural products 30,31 . Principal component analysis (PCA) utilizes a defined set of molecular descriptors, such as physicochemical properties, to represent each component compound as a vector in n-dimensional space.…”