MMP-Cliffs: Systematic Identification of Activity Cliffs on the Basis of Matched Molecular Pairs

Abstract

Activity cliffs are generally defined as pairs of structurally similar compounds having large differences in potency. The analysis of activity cliffs is of general interest because structure-activity relationship (SAR) determinants can often be deduced from them. Critical questions for the study of activity cliffs include how similar compounds should be to qualify as cliff partners, how similarity should be assessed, and how large potency differences between participating compounds should be. Thus far, activity cliffs have mostly been defined on the basis of calculated Tanimoto similarity values using structural descriptors, especially 2D fingerprints. As any theoretical assessment of molecular similarity, this approach has its limitations. For example, calculated Tanimoto similarities might often be difficult to reconcile and interpret from a chemical perspective, a point of critique frequently raised in medicinal chemistry. Herein, we have explored activity cliffs by considering well-defined substructure replacements instead of calculated similarity values. For this purpose, the matched molecular pair (MMP) formalism has been applied. MMPs were systematically derived from public domain compounds, and activity cliffs were extracted from them, termed MMP-cliffs. The frequency of cliff formation was determined for compounds active against different targets, MMP-cliffs were analyzed in detail, and re-evaluated on the basis of Tanimoto similarity. In many instances, chemically intuitive activity cliffs were only detected on the basis of MMPs, but not Tanimoto similarity.

Structural and Activity Profile Relationships Between Drug Scaffolds

“…The exchange of a pair of substructures that transforms compounds into each other is termed a chemical transformation (24). Three size restrictions were applied to limit structural differences between compounds to small replacements (typically involving R-groups) (25). First, the invariant core fragment was required to have at least twice the size of each exchanged fragment.…”

Advancing the activity cliff concept, part II

“…The formation of an MMP can thus be considered as a possible similarity criterion for activity cliff formation. To define activity cliffs, transformation size-restricted MMPs have been introduced in which transformations are limited to small and chemically meaningful replacements 7 . Accordingly, transformation size-restricted MMPs mostly account for structural analogs.…”

Activity cliff clusters as a source of structure–activity relationship information

“…Following our approach, structural relationships are established by applying a modified matched molecular pair (MMP) formalism [4,5]. An MMP represents a pair of compounds that are only distinguished by a structural change at a single site [4].…”

“…An MMP represents a pair of compounds that are only distinguished by a structural change at a single site [4]. In addition, we limit such changes to small replacements typically observed in analog series by applying transformation size restrictions to MMPs [5]. Pairs of active compounds forming transformation size-restricted MMPs and having an at least 100-fold difference in potency are termed MMP-cliffs [5].…”

“…In addition, we limit such changes to small replacements typically observed in analog series by applying transformation size restrictions to MMPs [5]. Pairs of active compounds forming transformation size-restricted MMPs and having an at least 100-fold difference in potency are termed MMP-cliffs [5]. These MMP-cliffs represent our preferred AC definition that is consistently applied in the following.…”