SHOP: A Method For Structure‐Based Fragment and Scaffold Hopping

Fontaine, Fabien; Cross, Simon; Plasencia, Guillem; Pastor, Manuel; Zamora, Ismael

doi:10.1002/cmdc.200800355

Cited by 14 publications

(11 citation statements)

References 51 publications

(42 reference statements)

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“…The fact that the property space of the binding cavities does not completely match the property space of the ligands has intriguing implications for ligand-based and structure-based design of novel ligands in drug discovery programs, since it indicates that ligands could be developed with very different binding modes from those of known ligands. One way to address this possibility would be to use fragment-based screening methods, either virtual ( e.g ., hot spot approaches) or experimental ( e.g ., nuclear magnetic resonance screening), to explore binding cavities and identify such potential ligands 67–69…”

Section: Resultsmentioning

confidence: 99%

Mapping of ligand‐binding cavities in proteins

2009

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The complex interactions between proteins and small organic molecules (ligands) are intensively studied because they play key roles in biological processes and drug activities. Here, we present a novel approach to characterise and map the ligand-binding cavities of proteins without direct geometric comparison of structures, based on Principal Component Analysis of cavity properties (related mainly to size, polarity and charge). This approach can provide valuable information on the similarities, and dissimilarities, of binding cavities due to mutations, between-species differences and flexibility upon ligand-binding. The presented results show that information on ligand-binding cavity variations can complement information on protein similarity obtained from sequence comparisons. The predictive aspect of the method is exemplified by successful predictions of serine proteases that were not included in the model construction. The presented strategy to compare ligand-binding cavities of related and unrelated proteins has many potential applications within protein and medicinal chemistry, for example in the characterisation and mapping of “orphan structures”, selection of protein structures for docking studies in structure-based design and identification of proteins for selectivity screens in drug design programs.

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Section: Resultsmentioning

confidence: 99%

Mapping of ligand‐binding cavities in proteins

2009

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“…SBs are interpreted as different structures depending on chirality (L, D or undefined) and position in the peptide (N-terminal, C-terminal, in the middle). For each SB, additional information is stored in the database such as InchiKey and Inchi, 2D structure, atom mapping and connectivity, physico-chemical properties and pharmacophoric properties described through molecular descriptors calculated by VolSurf [ 29 ] and SHOP software [ 30 ] ( Fig 3 ). Each connection of SBs is annotated by two connected structural blocks, bond type and two connected atoms which help to identify the direction of the connection.…”

Section: Methodsmentioning

confidence: 99%

Software-aided approach to investigate peptide structure and metabolic susceptibility of amide bonds in peptide drugs based on high resolution mass spectrometry

et al. 2017

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Interest in using peptide molecules as therapeutic agents due to high selectivity and efficacy is increasing within the pharmaceutical industry. However, most peptide-derived drugs cannot be administered orally because of low bioavailability and instability in the gastrointestinal tract due to protease activity. Therefore, structural modifications peptides are required to improve their stability. For this purpose, several in-silico software tools have been developed such as PeptideCutter or PoPS, which aim to predict peptide cleavage sites for different proteases. Moreover, several databases exist where this information is collected and stored from public sources such as MEROPS and ExPASy ENZYME databases. These tools can help design a peptide drug with increased stability against proteolysis, though they are limited to natural amino acids or cannot process cyclic peptides, for example. We worked to develop a new methodology to analyze peptide structure and amide bond metabolic stability based on the peptide structure (linear/cyclic, natural/unnatural amino acids). This approach used liquid chromatography / high resolution, mass spectrometry to obtain the analytical data from in vitro incubations. We collected experimental data for a set (linear/cyclic, natural/unnatural amino acids) of fourteen peptide drugs and four substrate peptides incubated with different proteolytic media: trypsin, chymotrypsin, pepsin, pancreatic elastase, dipeptidyl peptidase-4 and neprilysin. Mass spectrometry data was analyzed to find metabolites and determine their structures, then all the results were stored in a chemically aware manner, which allows us to compute the peptide bond susceptibility by using a frequency analysis of the metabolic-liable bonds. In total 132 metabolites were found from the various in vitro conditions tested resulting in 77 distinct cleavage sites. The most frequent observed cleavage sites agreed with those reported in the literature. The main advantages of the developed approach are the abilities to elucidate metabolite structure of cyclic peptides and those containing unnatural amino acids, store processed information in a searchable format within a database leading to frequency analysis of the labile sites for the analyzed peptides. The presented algorithm may be useful to optimize peptide drug properties with regards to cleavage sites, stability, metabolism and degradation products in drug discovery.

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“…Several investigations have demonstrated that simple molecular fingerprint descriptors are suitable for scaffold hopping [159][160][161], sometimes also combined with machine-learning methods [162,163]. Several approaches have been proposed based on the idea to replace a central scaffold of a molecule by novel scaffolds having the same exit vectors [164][165][166][167], and, depending on the approach, pharmacophore or property field similarity of the novel scaffold to the known reference scaffold.…”

Section: Data Mining For Promising Library Design Starting Pointsmentioning

confidence: 99%

Recent Trends and Observations in the Design of High-Quality Screening Collections

Renner¹,

Popov

Schuffenhauer

et al. 2011

Future Med. Chem.

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The design of a high-quality screening collection is of utmost importance for the early drug-discovery process and provides, in combination with high-quality assay systems, the foundation of future discoveries. Herein, we review recent trends and observations to successfully expand the access to bioactive chemical space, including the feedback from hit assessment interviews of high-throughput screening campaigns; recent successes with chemogenomics target family approaches, the identification of new relevant target/domain families, diversity-oriented synthesis and new emerging compound classes, and non-classical approaches, such as fragment-based screening and DNA-encoded chemical libraries. The role of in silico library design approaches are emphasized.

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SHOP: A Method For Structure‐Based Fragment and Scaffold Hopping

Cited by 14 publications

References 51 publications

Mapping of ligand‐binding cavities in proteins

Mapping of ligand‐binding cavities in proteins

Software-aided approach to investigate peptide structure and metabolic susceptibility of amide bonds in peptide drugs based on high resolution mass spectrometry

Recent Trends and Observations in the Design of High-Quality Screening Collections

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