Scaffold diversity of exemplified medicinal chemistry space

Abstract

The scaffold diversity of 7 representative commercial and proprietary compound libraries is explored for the first time using both Murcko frameworks and Scaffold Trees. We show that Level 1 of the Scaffold Tree is useful for the characterization of scaffold diversity in compound libraries and offers advantages over the use of Murcko frameworks. This analysis also demonstrates that the majority of compounds in the libraries we analyzed contain only a small number of well represented scaffolds and that a high percentage of singleton scaffolds represent the remaining compounds. We use Tree Maps to clearly visualize the scaffold space of representative compound libraries, for example, to display highly populated scaffolds and clusters of structurally similar scaffolds. This study further highlights the need for diversification of compound libraries used in hit discovery by focusing library enrichment on the synthesis of compounds with novel or underrepresented scaffolds.

Figure 1

An interpretation of the Markush structure as described in the 1924 Markush patent.(3)

Figure 2

The HSP90 inhibitor NVP-AUY922 depicted using different scaffold representations.

Figure 3

Scaffold Tree analysis: cumulative scaffold frequency plot showing the distribution of compounds over Level 1 scaffolds in the ICRSC, VC, ICRFL, CHEMBL, DBSM, DBAD, and BIOFOC data sets.

Figure 4

Murcko framework analysis: cumulative scaffold frequency plot showing the distribution of compounds over Murcko framework scaffolds in the ICRSC, VC, ICRFL, CHEMBL, DBSM, DBAD, and BIOFOC data sets.

Figure 5

Examples of how compounds of different complexity are represented by Murcko frameworks and Level 1 scaffolds. Each molecule had n+1 Levels numbered sequentially from Level 0 (the single remaining ring) up to Level n (the whole molecule) where Level n-1 is the Murcko framework: compound a: A typical leadlike/druglike chemical structure; compound b: A typical fragmentlike chemical structure.

Figure 6

Example Tree Map. The colored circles represent scaffolds and are labeled with their scaffold frequency. The area and color of the circles relate to the scaffold frequency. Scaffold circles are grouped into gray circles if the scaffolds are in the same cluster.

Figure 7

Tree Map of the VC data set Level 1 scaffolds. Scaffolds are represented by colored circles, the area and color of the circles relate to the scaffold frequency, gray circles represent clusters of scaffolds. Tree Maps illustrate the large proportion of singleton scaffolds in the data sets (many small white circles) and the presence of highly populated scaffolds (few large green circles).

Figure 8

Tree Map of the DBSM data set Level 1 scaffolds. Scaffolds are represented by colored circles, the area and color of the circles relate to the scaffold frequency, gray circles represent clusters of scaffolds. Tree Maps illustrate the large proportion of singleton scaffolds in the data sets (many small white circles) and the presence of highly populated scaffolds (few large green circles).

Figure 9

Tree Map of the BIOFOC data set Level 1 scaffolds. Scaffolds are represented by colored circles, the area and color of the circles relate to the scaffold frequency, gray circles represent clusters of scaffolds. Tree Maps illustrate the large proportion of singleton scaffolds in the data sets (many small white circles) and the presence of highly populated scaffolds (few large green circles).