Structure Modification in Chemical Databases

Kenny, Peter W.; Sadowski, Jens

doi:10.1002/3527603743.ch11

Cited by 188 publications

(225 citation statements)

References 10 publications

(15 reference statements)

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“…Matched molecular pair (MMP) relationship: an MMP is defined as a pair of compounds that only differ by a structural change at a single site (23). The exchange of a pair of substructures that transforms compounds into each other is termed a chemical transformation (24).…”

Section: Structural Relationshipsmentioning

confidence: 99%

Structural and Activity Profile Relationships Between Drug Scaffolds

Bajorath

2015

AAPS J

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Abstract. Core structures of current drugs have been assembled and their structural relationships and activity profiles have been explored. Drug scaffolds were frequently involved in different types of structural relationships. In addition, a variety of activity profile relationships between structurally related drug scaffolds were detected, ranging from closely overlapping to distinct profiles. Furthermore, when structural and activity profile relationships of scaffolds from drugs and bioactive compounds were compared, systematic differences were detected. Consensus activity profiles were introduced as a new approach for the qualitative and quantitative assessment of activity similarity of structurally related drugs represented by the same scaffold. On the basis of consensus activity profiles, scaffolds representing drugs active against distinct targets can be distinguished from drugs having similar target profiles and target hypotheses can be derived for individual drugs. Given the results of our analysis, drug scaffolds have been systematically organized according to structural and activity profile criteria. Our scaffold sets and the associated information are made freely available.

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Section: Structural Relationshipsmentioning

confidence: 99%

Structural and Activity Profile Relationships Between Drug Scaffolds

Bajorath

2015

AAPS J

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“…To convey SAR information, matrix cells representing data set compounds are color-coded according to compound potency. The methodological basis for compound series identification and organization was provided by the matched molecular pair (MMP) concept 7 . An MMP is defined as a pair of compounds that differ only at a single site 7 .…”

Section: Compound Structure Analysis and Organizationmentioning

confidence: 99%

“…The methodological basis for compound series identification and organization was provided by the matched molecular pair (MMP) concept 7 . An MMP is defined as a pair of compounds that differ only at a single site 7 . Compounds in MMPs can be interconverted by the exchange of a substructure, termed a chemical transformation 8 .…”

Section: Compound Structure Analysis and Organizationmentioning

confidence: 99%

The ‘SAR Matrix’ method and its extensions for applications in medicinal chemistry and chemogenomics

Gupta-Ostermann

Bajorath

2014

F1000Res

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“…Matched molecular pairs (MMPs) are defined as pairs of compounds that differ only by a structural change at a single site (16), i.e., the exchange of a substructure, termed a chemical transformation (17). MMPs were systematically calculated for compounds in all target sets using an in-house implementation of the algorithm by Hussain and Rea (17) based on the OEChem toolkit (18).…”

Section: Matched Molecular Pairsmentioning

confidence: 99%

Formation of Activity Cliffs Is Accompanied by Systematic Increases in Ligand Efficiency from Lowly to Highly Potent Compounds

Léon

Bajorath

2014

AAPS J

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Abstract. Activity cliffs (ACs) are defined as pairs of structurally similar compounds sharing the same biological activity but having a large difference in potency. Therefore, ACs are often studied to rationalize structure-activity relationships (SARs) and aid in lead optimization. Hence, the AC concept plays an important role in compound development. For compound optimization, ligand efficiency (LE) represents another key concept. LE accounts for the relation between compound potency and mass. A major goal of lead optimization is to increase potency and also LE. Despite their high relevance for drug development, the AC and LE concepts have thus far not been considered in combination. It is currently unknown how compounds forming ACs might be related in terms of LE. To explore this question, ACs were systematically identified on the basis of high-confidence activity data and LE values for cliff partners were determined. Surprisingly, a significant increase in LE was generally detected for highly potent cliff partners compared to their lowly potent counterparts, regardless of the compound classes and their targets. Hence, ACs reveal chemical modifications that determine SARs and improve LE. These findings further increase the attractiveness of AC information for compound optimization and development.

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Structure Modification in Chemical Databases

Cited by 188 publications

References 10 publications

Structural and Activity Profile Relationships Between Drug Scaffolds

Structural and Activity Profile Relationships Between Drug Scaffolds

The ‘SAR Matrix’ method and its extensions for applications in medicinal chemistry and chemogenomics

Formation of Activity Cliffs Is Accompanied by Systematic Increases in Ligand Efficiency from Lowly to Highly Potent Compounds

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