Exploring Chemical Rings in a Simple Topological-Descriptor Space

Abstract

A new method for organizing chemical rings based on their topology is presented. It uses three simple descriptors that characterize separate aspects of ring topology. These descriptors are integers and can thus be interpreted as the coordinates of discrete cells in a three-dimensional space. The descriptor values of any ring topology correspond to the coordinates of some cell. A database of rings can be distributed in this descriptor space by assigning each of them to the corresponding cell. This approach is applied to a database of 40 182 different ring topologies, derived from a comprehensive collection of chemical rings extracted from the CAS Registry File. This database is distributed among 7387 cells, and the population statistics and spatial distribution of these cells are discussed. An examination of selected cells shows that ring topologies which are similar tend to be close together in descriptor space. Some results of using this space to study ring diversity are presented. It is found that the distribution of the ring-topology database is not highly compact but has many significant voids. It is also found that the distribution of medicinally relevant rings in this space shows the influence of certain structural constraints on drug molecules.

Structural Diversity of Organic Chemistry. A Scaffold Analysis of the CAS Registry

“…A number of studies have analyzed diversity based on the ring systems in structures. [5][6][7][8][9][10][11] 10.1021/jo8001276 CCC: $40.75  2008 American Chemical Society is that structures having such features in common often belong to the same chemical family.…”

Quest for the Rings. In Silico Exploration of Ring Universe To Identify Novel Bioactive Heteroaromatic Scaffolds

“…Principal components generated from these properties correlated with the in vitro biological activity of ring systems under study. Lipkus 6 presented a method for organizing ring systems based on their topology. Three simple descriptors that characterize separate aspects of ring topology were used in the study.…”

Scaffold Searching: Automated Identification of Similar Ring Systems for the Design of Combinatorial Libraries

“…When many ring systems satisfy the search constraints, as with target-2, then some form of hit-list post-processing may be required (Step 6 in Figure 2). Approaches that could be considered include clustering the output using any rapidly-computed similarity measure (such as the atom-mapping similarities or 2D fingerprint similarities) or grouping them using high-level ring descriptors such as those suggested by Bedrosian et al [3], Nilakantan et al [5] or Lipkus [9]; alternatively, a more precise ranking of the search output could be obtained by calculating the volume overlap for each alignment and then ranking the database ring systems in decreasing goodness-of-fit.…”

“…The important role played by ring systems in drug discovery has meant that much effort has been devoted over very many years to the development of automated methods for their identification, representation and searching (see, e.g., [1][2][3][4][5][6][7][8][9]). Recent developments in combinatorial chemistry mean that it is now possible to synthesise large libraries of compounds, consisting of a central ring system to which are attached a range of different substituents [10].…”