![]() In the end, a tree-like hierarchy results with the individual ring systems as roots at the top, and their combinations in more complex scaffolds on the following levels. Via a substructure search, the scaffold hierarchy is constructed in the second step by linking parent and child scaffold if the smaller parent scaffold is a substructure of the bigger child scaffold. ![]() The process is finished when only the individual ring systems are left. After the removal of one ring, linker atoms that have become side chains are also removed. isolated single rings or fused multiple rings that share bonds or atoms, from the original scaffold. This is done by generating all smaller scaffolds that can result from the stepwise removal of ring systems, i.e. To build a scaffold hierarchy, the original scaffold extracted from each molecule is dissected into its smaller parent scaffolds first. Non-cyclic molecules are taken into consideration as well and are assigned scaffolds based on their multiple bonds. in their hierarchical scaffold clustering (HierS) approach use a scaffold definition similar to Murcko frameworks but additionally include all atoms that are directly attached to rings and linkers via multiple bonds. They used these concepts to assign molecular equivalence numbers to molecular structures and thus classify them within chemical libraries. Įarly work to this end was done by Xu and Johnson, who developed multiple concepts of dissecting Murcko frameworks into constituting ring systems or abstracting them into reduced representations. Therefore, multiple approaches have been developed for organising molecular scaffolds in a graph-based structure to relate similar scaffolds to each other and to create a systematic scaffold hierarchy. a benzene ring in drug design or a sugar moiety in NP research, can lead to very similar molecules not being grouped together due to non-equivalent scaffolds. In addition to ignoring all non-cyclic molecules, the Murcko framework has one major drawback: small changes in the ring structure or the addition of a cyclic substituent, e.g. The authors used their framework definitions to assess the structural diversity of a set of drug molecules. In addition to the Murcko framework definition representing molecular properties like atomic elements and bond multiplicities, Bemis and Murcko introduced a more abstract representation that reduced each atom in the framework to a simple graph node and each bond to a simple graph vertex, called graph framework or archetype. Excluded from the scaffold are all terminal side chains. ![]() According to this concept, a scaffold consists of all the rings in a molecule and the non-cyclic chains connecting them, called linkers. The first general definition of a molecular scaffold was the Murcko framework developed by Bemis and Murcko in 1996. Within NP chemical space, macrocyclic structures or cyclic peptides are of specific interest for these medicinal chemistry purposes. Īnother application of scaffold-based methods is identifying privileged substructures in active molecules or NP that can be used as lead structures in the development of new drugs. ![]() In cheminformatics, scaffold-based approaches can be applied for the analysis of high-throughput screening (HTS) data, mapping and visualising chemical spaces, or even train-test splits of molecular data sets for machine learning projects. The intuitive chemical scaffold concept can also be utilised for classification purposes, especially in natural product (NP) research. And structures in chemical patents are often defined analogously as Markush structures. Combinatorial chemistry makes use of the concept in designing compound libraries by substituting a set of scaffolds with combinations of different side chains. For this reason, developing new drug molecules with different cores but similar biological activities has been termed “scaffold hopping”. In drug design, the scaffold of a molecule is considered the main structure that determines its shape and places the functional moieties into the right positions to interact with the target. Molecular scaffolds, defined as the core structures of molecules and also referred to as chemotypes or frameworks in some studies, are a concept used in many areas of chemistry.
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