Advancing the activity cliff concept, part II.

Dagmar Stumpfe,Jürgen Bajorath,Antonio De La Vega De León,Dilyana Dimova

doi:10.12688/f1000research.4057

Abstract

We present a follow up contribution to further complement a previous commentary on the activity cliff concept and recent advances in activity cliff research. Activity cliffs have originally been defined as pairs of structurally similar compounds that display a large difference in potency against a given target. For medicinal chemistry, activity cliffs are of high interest because structure-activity relationship (SAR) determinants can often be deduced from them. Herein, we present up-to-date results of systematic analyses of the ligand efficiency and lipophilic efficiency relationships between activity cliff-forming compounds, which further increase their attractiveness for the practice of medicinal chemistry. In addition, we summarize the results of a new analysis of coordinated activity cliffs and clusters they form. Taken together, these findings considerably add to our evaluation and current understanding of the activity cliff concept. The results should be viewed in light of the previous commentary article.

Highlights

Over the past decade, the activity cliff concept has been increasingly discussed in the chemoinformatics and medicinal chemistry literature[1,2,3]
We present a follow up to this commentary, which has been catalyzed by the availability of new results concerning the ligand efficiency and lipophilic efficiency of activity cliff partners as well as the topology of coordinated activity cliffs formed across currently available bioactive compounds
The analysis revealed that the formation of 99.1% of all activity cliffs across different targets was accompanied by consistent increases in ligand efficiency (LE) values between lowly and highly potent cliff partners, with, on average, ∆LE = 6.2514

Summary

Introduction

The activity cliff concept has been increasingly discussed in the chemoinformatics and medicinal chemistry literature[1,2,3]. Series of highly and lowly potent analogs have been identified in different data sets that formed multiple overlapping activity cliffs[16] These cliff arrangements have been termed coordinated activity cliffs[17]. Different from clusters with star topology, chains with more than three compounds and rectangles require the presence of alternating highly and lowly potent compounds forming sequences of activity cliffs or circular arrangements, which are less likely than stars. For a detailed characterization of the global activity cliff network and individual cluster topologies, the interested reader is referred to the original publication[18]

Conclusions

Maggiora GM

Findings

12. Shultz MD