Bioactivity-guided mapping and navigation of chemical space

Renner, Steffen; Otterlo, Willem A. L. van; Seoane, Marta Dominguez; Möcklinghoff, Sabine; Hofmann, Bettina; Wetzel, Stefan; Schuffenhauer, Ansgar; Ertl, Peter; Oprea, Tudor I.; Steinhilber, Dieter; Brunsveld, Luc; Rauh, Daniel; Waldmann, Herbert

doi:10.1038/nchembio.188

Cited by 134 publications

(101 citation statements)

References 26 publications

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“…Other commonly used methods include the calculation of normalized principle moment-of-inertia ratios for the assessment of molecular shape diversity 34,51 and comparison of the polar surface areas of molecules in the library (the polar surface area is a key feature in terms of ligand -receptor binding; indeed, diverse biological activity has been associated with small molecules with diverse polar surface areas) 51 . Recently a computer-based tool called ' Scaff old Hunter ' has been developed which extracts the molecular scaff olds present in a compound collection and correlates the relationship between them in a hierarchical tree-like arrangement 63,64 . Not only does this allow a more quantitative, less-subjective assessment of the scaff old diversity contained within a particular chemical …”

Section: Assessing Diversitymentioning

confidence: 99%

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

2010

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Biologically active molecules can be identifi ed through the screening of small-molecule libraries. Defi ciencies in current compound collections are evidenced by the continuing decline in drugdiscovery successes. Typically, such collections are comprised of large numbers of structurally similar compounds. A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and thus function, is crucial. Diversity-oriented synthesis (DOS) aims to generate such structural diversity in an effi cient manner. Recent years have witnessed signifi cant achievements in the fi eld, which help to validate the usefulness of DOS as a tool for the discovery of novel, biologically interesting small molecules.S mall molecular mass chemical entities (so-called small molecules) have always been of interest in chemistry and biology because of their ability to exert powerful eff ects on the functions of macromolecules that comprise living systems 1 -3 . Indeed, the small-molecule modulation of protein function represents the basis for both medicinal chemistry (wherein molecules are sought to chemically modify disease states) and chemical genetics (wherein molecules are used as ' probes ' to study biological systems 3 -8 . Such chemical modulators are most commonly identifi ed by screening collections or ' libraries ' of small molecules. However, a crucial consideration is what compounds to use 3,9,10 . A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and more importantly function, is a crucial consideration. Th e effi cient creation of functionally diverse small-molecule collections presents a formidable challenge.Traditionally, when a specifi c biological molecule or family of molecules is targeted, the compounds used in the screening process are usually selected or designed on the basis of knowledge of the target structure or the structure of known natural ligands 3,9,11 . Th e selection criteria are dramatically complicated if the subsequent screening is ' unbiased ' ; that is, when the precise nature of the biological target is unknown (for example, in a random drug-discovery screen) 4,3,12 . In such situations, the structural features required in the small molecules cannot be defi ned a priori and it can be argued that the screening of a library of compounds that has been designed to interact with one specifi c biological target (or family of related targets) is not logical, whereas the random screening of many such ' focused ' collections can be extremely time and cost demanding.In general, the identifi cation of biologically active small molecules may be aided by screening functionally diverse compound libraries (that is, libraries that display a broad range of biological activities), as it has been argued that a greater sample of the bioactive chemical universe (that is, of all bioactive molecules) increases the chance of identifying a compound with the desired properties 3,10,13,14 . As a corollary, ...

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Section: Assessing Diversitymentioning

confidence: 99%

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

2010

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“…We note that activity profiles for largescale promiscuity analysis are generated from positive activity data (in the absence of negative data, as further discussed below). The activity profile definition as reported herein has been consistently applied in previous studies to assess the biological activity and the degree of promiscuity associated with scaffolds or chemotypes (7,21,29,30). In our current analysis, activity profiles were used for drug scaffold promiscuity assessment.…”

Section: Activity Profilesmentioning

confidence: 99%

“…According to the definition that is most widely applied in medicinal chemistry, originally introduced by Bemis and Murcko (3), scaffolds are extracted from compounds by removing all substituents (R-groups), while retaining aliphatic linkers between ring systems (3). One of the primary goals of scaffold analysis is the association of molecular building blocks or core structures with specific biological activities (4)(5)(6)(7). Knowledge of such preferred core structures is thought to be of high relevance for target-or target family-directed compound design (2)(3)(4).…”

Section: Introductionmentioning

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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“…Simplification of parent natural product architectures has previously been shown to afford synthetically tractable entities with modest yet sustained bioactivity 14. Hence, for our chemical‐genomics‐inspired target‐prediction program, we identified the fragment‐like anticancer agent piperlongumine (PL, Figure 1) as a suitable chemical tool.…”

mentioning

confidence: 99%

Unveiling (−)‐Englerin A as a Modulator of L‐Type Calcium Channels

et al. 2016

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The voltage‐dependent L‐type Ca2+channel was identified as a macromolecular target for (−)‐englerin A. This finding was reached by using an unprecedented ligand‐based prediction platform and the natural product piperlongumine as a pharmacophore probe. (−)‐Englerin A features high substructure dissimilarity to known ligands for voltage‐dependent Ca2+ channels, selective binding affinity for the dihydropyridine site, and potent modulation of calcium signaling in muscle cells and vascular tissue. The observed activity was rationalized at the atomic level by molecular dynamics simulations. Experimental confirmation of this hitherto unknown macromolecular target expands the bioactivity space for this natural product and corroborates the effectiveness of chemocentric computational methods for prioritizing target‐based screens and identifying binding counterparts of complex natural products.

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Bioactivity-guided mapping and navigation of chemical space

Cited by 134 publications

References 26 publications

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

Structural and Activity Profile Relationships Between Drug Scaffolds

Unveiling (−)‐Englerin A as a Modulator of L‐Type Calcium Channels

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