Integration of fragment screening and library design

Siegal, Gregg; Ab, Eiso; Schultz, Jan

doi:10.1016/j.drudis.2007.08.005

Cited by 125 publications

(101 citation statements)

References 44 publications

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“…Six of these 19 compounds are active at concentrations below 100 µM against PM I, PM II, and PM IV (compounds 1-6 in Table 3 and Figure 3). Therefore, the in silico screening approach is much more effective than medium-and high-throughput screening procedures in vitro, for which hit rates between 0.1% and 5% have been reported [19].…”

Section: Inhibitor Discovery By Fragment-based Docking and Consensus mentioning

confidence: 99%

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Friedman

Caflisch

2009

ChemMedChem

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Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are therefore promising targets for developing drugs against malaria. We have discovered six inhibitors of PM II by high‐throughput fragment‐based docking of a diversity set of ∼40 000 molecules, and consensus scoring with force field energy functions. Using the common scaffold of the three most active inhibitors (IC50=2–5 μM), another seven inhibitors were identified by substructure search. Furthermore, these 13 inhibitors belong to at least three different classes of compounds. The in silico approach was very effective since a total of 13 active compounds were discovered by testing only 59 molecules in an enzymatic assay. This hit rate is about one to two orders of magnitude higher than those reported for medium‐ and high‐throughput screening techniques in vitro. Interestingly, one of the inhibitors identified by docking was halofantrine, an antimalarial drug of unknown mechanism. Explicit water molecular dynamics simulations were used to discriminate between two putative binding modes of halofantrine in PM II.

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Section: Inhibitor Discovery By Fragment-based Docking and Consensus mentioning

confidence: 99%

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Friedman

Caflisch

2009

ChemMedChem

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“…Subsequent elaboration of the fragment can then introduce interactions and compound features that provide the required affi nity and selectivity while conventional medicinal chemistry considerations optimize drug-like properties 81 . As with any screening approach, library design is a critical consideration in order to ensure that relevant hits of suffi ciently high quality can be obtained 81,82 . Small fragments have an increased probability of binding to a given target than do larger, more complex molecules 83 ; increased molecular complexity (and size) reduces the probability of fi nding leads, because the decoration of compounds increases the chance that useful interactions will not be made by randomly chosen ligands 81 .…”

Section: Conclusion and Future Perspectivesmentioning

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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“…The value IC 50 or EC 50 B 10 lM was chosen as activity threshold for fragment-type activity [28]. The ten targets were associated with nine drugs belonging to the 200 top-selling drugs in 2010.…”

Section: Virtual Screening In Mqn-spacementioning

confidence: 99%

“…The following paper details the MQN-analysis of the fragment subset of PubChem comprising all molecules with up to 20 non-hydrogen atoms (hac B 20), which corresponds to the broadest definition of fragments [28]. MQN-maps produced by principal component analysis (PCA) of the MQN data and representation of the (PC1, PC2), (PC1, PC3) and (PC2, PC3) planes illustrate the structural diversity of PubChem fragments, and how the subsets of molecules fulfilling the increasingly restrictive criteria of Lipinski's ''rule of five'', Oprea's ''lead-likeness'' and Congreve's''rule of three'' are distributed [29].…”

Section: Introductionmentioning

confidence: 99%

Visualisation of the chemical space of fragments, lead-like and drug-like molecules in PubChem

Deursen

Blum

Reymond

2011

J Comput Aided Mol Des

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The 4.5 million organic molecules with up to 20 non-hydrogen atoms in PubChem were analyzed using the MQN-system, which consists in 42 integer value descriptors of molecular structure. The 42-dimensional MQN-space was visualised by principal component analysis and representation of the (PC1, PC2), (PC1, PC3) and (PC2, PC3) planes. The molecules were organized according to ring count (PC1, 38% of variance), the molecular size (PC2, 25% of variance), and the H-bond acceptor count (PC3, 12% of variance). Compounds following Lipinski's bioavailability, Oprea's lead-likeness and Congreve's fragment-likeness criteria formed separated groups in MQN-space visible in the (PC2, PC3) plane. MQN-similarity searches of the 4.5 million molecules (see the browser available at www.gdb.unibe.ch) gave significant enrichment factors for recovering groups of fragment-sized bioactive compounds related to ten different biological targets taken from Chembl, allowing leadhopping relationships not seen with substructure fingerprint similarity searches. The diversity of different compound series was analyzed by MQN-distance histograms.

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Integration of fragment screening and library design

Cited by 125 publications

References 44 publications

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

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

Visualisation of the chemical space of fragments, lead-like and drug-like molecules in PubChem

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