“Molecular Anatomy”: a new multi-dimensional hierarchical scaffold analysis tool

Abstract

The scaffold representation is widely employed to classify bioactive compounds on the basis of common core structures or correlate compound classes with specific biological activities. In this paper, we present a novel approach called “Molecular Anatomy” as a flexible and unbiased molecular scaffold-based metrics to cluster large set of compounds. We introduce a set of nine molecular representations at different abstraction levels, combined with fragmentation rules, to define a multi-dimensional network of hierarchically interconnected molecular frameworks. We demonstrate that the introduction of a flexible scaffold definition and multiple pruning rules is an effective method to identify relevant chemical moieties. This approach allows to cluster together active molecules belonging to different molecular classes, capturing most of the structure activity information, in particular when libraries containing a huge number of singletons are analyzed. We also propose a procedure to derive a network visualization that allows a full graphical representation of compounds dataset, permitting an efficient navigation in the scaffold’s space and significantly contributing to perform high quality SAR analysis. The protocol is freely available as a web interface at https://ma.exscalate.eu.

ProfhEX: AI-based platform for small molecules liability profiling

“…aromatic/aliphatic rings, amide bonds, etc.). PCA was not directly applied to individual compounds but to their "basic framework" scaffolds [35]. Starting from the widely accepted de nition of scaffold (which is generated by removing all side chains and terminal atoms), a basic framework brings an even higher level of abstraction, having all the atoms converted to carbons but still maintaining features such as rami cations, double and aromatic bonds.…”

Scaffold Generator - A Java library implementing molecular scaffold functionalities in the Chemistry Development Kit (CDK)

“…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. Therefore, multiple 4 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 [4,5,7,9,10,13,[24][25][26][27].…”

“…Possible functional extensions of Scaffold Generator include the incorporation of more abstract scaffold representations, based on the work by Xu and Johnson [25], and the possibility to build scaffold networks or trees encompassing multiple scaffold definitions of varying chemical resolution, like in Molecular Anatomy [26] or the tree-like classification of Medina-Franco et al [24]. A major addition to the functionality of Scaffold Generator would be the inclusion of analog series based scaffold methodologies.…”

Scaffold Generator: a Java library implementing molecular scaffold functionalities in the Chemistry Development Kit (CDK)

“…An even more extensive scaffold network approach was published recently by Manelfi et al named “Molecular Anatomy” [ 26 ]. While the aforementioned approaches mostly rely on one single scaffold definition, respectively, nine different scaffold types of different abstraction levels were introduced here.…”

“…Structural scaffold analyses are relevant in diverse areas of cheminformatics, e.g. clustering, visualisation of chemical spaces, and SAR analyses [ 4 – 10 , 26 , 30 ]. Hence, numerous open software tools for such purposes have been developed [ 28 , 29 , 39 – 44 ].…”