When looking for a new substance to act as a pharmaceutical agent, researchers have to sift through a lot of chemical structures to find good candidates. To help filter through the huge number of possible candidates, researchers at the Max Planck Institute of Molecular Physiology in Dortmund, Germany have developed a new application that matches the chemical space of a given compound to the possibility that it will bind to a protein in question. The Scaffold Hunter application, in addition to matching known compounds, can also suggest unknown yet unobserved ones that may become possible matches to a protein.
More details from the Max Planck Society:
The scientists focus on the medically relevant section of the chemical space, in which molecules contain ring-shaped structures. To do this, they reduce the molecules to their characteristic scaffolds. Scaffold Hunter then orders these structures in a kind of family tree based on their similarities: the program assigns smaller ‘parent’ scaffolds to each scaffold by gradually removing rings from the original ‘child’ scaffold. This generates innumerable parent-child relationships – structurally related molecules of varying complexity. The advantage lies in the fact that chemically similar compounds are very likely to display similar biological activity.
"These structurally-based lineages form the branches of the tree," explains Stefan Wetzel: "With the help of Scaffold Hunter we move along the branches from complex to increasingly simple structures which may be similar in their effect." Thus, the researchers identify structurally simple scaffolds with promising characteristics as the starting point in the quest for new active agents: chemists can then vary the scaffolds with different appendages to synthesize the optimal active agent. Scaffold Hunter can also be used to predict bioactive molecules that do not arise in nature but are very likely to display similar activity to related natural molecules, as the program also creates and visualizes virtual scaffolds. The researchers immediately demonstrated how efficiently the program works by discovering new inhibitors of pyruvate kinase. The inhibition of this enzyme is seen as a promising approach to the treatment of cancer and malaria.
An even more detailed search can be carried out if the scientist can enter information about biological activity – if available – at the beginning of the navigation process. In this case, Scaffold Hunter only links the scaffolds that are known to display the same biological activity to the branches. As a result, these branches are very likely to bear fruit: active substances are probably also located in the branches between the substances whose biological activity is already known. "In this way, we tracked down new inhibitors for 2-lipoxygenase and the oestrogen receptor alpha," says Steffen Renner, a former researcher at the Max Planck Institute and now an employee of the Novartis pharmaceutical concern. 5-lipoxygenase is a target protein in the treatment of inflammation and bladder cancer, while the oestrogen receptor alpha is an important starting point in the treatment of breast cancer.
Press release: Navigating in the ocean of molecules
Image: The search for active agents in the tree of structures: Basic chemical scaffolds are linked initially on the basis of their structural similarity. Compounds that influence the enzyme pyruvate kinase are shown in blue, the virtual scaffolds in grey. Variants of the virtual scaffold shaded in red (top right) were tested for their biological potency and pointed to other active substances (bottom right)).
Abstract in Nature Chemical Biology:Bioactivity-guided mapping and navigation of chemical space