Natural-product-derived fragments for fragment-based ligand discovery

Abstract

Fragment-based ligand and drug discovery predominantly employs sp(2)-rich compounds covering well-explored regions of chemical space. Despite the ease with which such fragments can be coupled, this focus on flat compounds is widely cited as contributing to the attrition rate of the drug discovery process. In contrast, biologically validated natural products are rich in stereogenic centres and populate areas of chemical space not occupied by average synthetic molecules. Here, we have analysed more than 180,000 natural product structures to arrive at 2,000 clusters of natural-product-derived fragments with high structural diversity, which resemble natural scaffolds and are rich in sp(3)-configured centres. The structures of the cluster centres differ from previously explored fragment libraries, but for nearly half of the clusters representative members are commercially available. We validate their usefulness for the discovery of novel ligand and inhibitor types by means of protein X-ray crystallography and the identification of novel stabilizers of inactive conformations of p38α MAP kinase and of inhibitors of several phosphatases.

The 'rule of three' for fragment-based drug discovery: where are we now?

“…Several groups have reported initiatives to construct libraries of three-dimensional fragments 7,8 (see the 3D Fragment Consortium website), often designed to target protein-protein interfaces (PPIs), in the belief that fragment-based screening is unlikely to yield hits unless more 'threedimensionality' can be incorporated into their fragments. Two assumptions seem to be implicit in this argument: first, that current fragment libraries are largely composed of 'flat structures'; and second, that pockets on PPIs are fundamentally different from other protein binding sites.…”

Opportunity Knocks: Organic Chemistry for Fragment‐Based Drug Discovery (FBDD)

“…[25] There have also been other initiatives to synthesise 3D fragments [26] including those based on natural products. [27] We welcome any initiatives that allow the synthesis of novel fragment-like molecules that retain the sampling advantages of fragments and offer ar ange of synthetically accessible vectors for future elaboration. In our laboratories it is common to increase 3D character during the fragment optimisation stage and even fragments lacking chiral centres may adopt 3D or chiral conformations when binding to protein targets.…”

25 Years of Small Molecular Weight Kinase Inhibitors: Potentials and Limitations

“…Those that bind in the presence of ATP (DFG-in conformation, such as MEK inhibitors) can be referred to as "allosteric backpocket DFG-in inhibitors". Alternatively, "allosteric back-pocket DFG-out inhibitors" can bind to the allosteric back-pocket in the absence of ATP (DFG-out conformation) and include allosteric inhibitors of insulin-like growth factor 1 receptor (IGF-1R) (Heinrich et al, 2010), FAK (Tomita et al, 2013), or p38 (Over et al, 2013). In the case of IGF-1R, the inhibitor binds in the DFG-out pocket and extends over the catalytic loop rather than pushing it out from underneath like the FAK inhibitor, requiring additional conformational changes (Tomita et al, 2013).…”