Exploring Activity Cliffs in Medicinal Chemistry

Matched molecular pairs (MMPs) are widely used in medicinal chemistry to study changes in compound properties including biological activity, which are associated with well-defined structural modifications. Herein we describe up-to-date versions of three MMP-based data sets that have originated from in-house research projects. These data sets include activity cliffs, structure-activity relationship (SAR) transfer series, and second generation MMPs based upon retrosynthetic rules. The data sets have in common that they have been derived from compounds included in the latest release of the ChEMBL database for which high-confidence activity data are available. Thus, the activity data associated with MMP-based activity cliffs, SAR transfer series, and retrosynthetic MMPs cover the entire spectrum of current pharmaceutical targets. Our data sets are made freely available to the scientific community.

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Recent Progress in Understanding Activity Cliffs and Their Utility in Medicinal Chemistry

Journal of Medicinal Chemistry ◽

10.1021/jm401120g ◽

2013 ◽

Vol 57 (1) ◽

pp. 18-28 ◽

Cited By ~ 128

Author(s):

Dagmar Stumpfe ◽

Ye Hu ◽

Dilyana Dimova ◽

Jürgen Bajorath

Keyword(s):

Recent Progress ◽

Medicinal Chemistry ◽

Activity Cliffs

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Advancing the activity cliff concept, part II

F1000Research ◽

10.12688/f1000research.3788.1 ◽

2014 ◽

Vol 3 ◽

pp. 75 ◽

Cited By ~ 16

Author(s):

Dagmar Stumpfe ◽

Antonio de la Vega de León ◽

Dilyana Dimova ◽

Jürgen Bajorath

Keyword(s):

Medicinal Chemistry ◽

Current Understanding ◽

Activity Relationship ◽

Ligand Efficiency ◽

Research Activity ◽

High Interest ◽

Structure Activity ◽

Activity Cliff ◽

Activity Cliffs

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.

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Matched molecular pair-based data sets for computer-aided medicinal chemistry

F1000Research ◽

10.12688/f1000research.3-36.v2 ◽

2014 ◽

Vol 3 ◽

pp. 36 ◽

Cited By ~ 2

Author(s):

Ye Hu ◽

Antonio de la Vega de León ◽

Bijun Zhang ◽

Jürgen Bajorath

Keyword(s):

Scientific Community ◽

Medicinal Chemistry ◽

Data Sets ◽

Research Projects ◽

High Confidence ◽

Activity Data ◽

Structural Modifications ◽

Matched Molecular Pairs ◽

Structure Activity ◽

Activity Cliffs

Matched molecular pairs (MMPs) are widely used in medicinal chemistry to study changes in compound properties including biological activity, which are associated with well-defined structural modifications. Herein we describe up-to-date versions of three MMP-based data sets that have originated from in-house research projects. These data sets include activity cliffs, structure-activity relationship (SAR) transfer series, and second generation MMPs based upon retrosynthetic rules. The data sets have in common that they have been derived from compounds included in the ChEMBL database (release 17) for which high-confidence activity data are available. Thus, the activity data associated with MMP-based activity cliffs, SAR transfer series, and retrosynthetic MMPs cover the entire spectrum of current pharmaceutical targets. Our data sets are made freely available to the scientific community.

Download Full-text