Scaffold‐Hopping: How Far Can You Jump?

Schneider, Gisbert; Schneider, Petra; Renner, Steffen

doi:10.1002/qsar.200610091

Cited by 139 publications

(63 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pharmacophore descriptors typically focus on the relative position of pharmacophore groups in the molecule, not paying much attention to the manner in which these are interconnected -the pharmacophoric pairs, [32,33] triplets [34,35] and 4-point descriptors, [36] which enables them to perform successful "scaffold hopping" (discovery of new scaffolds porting the given pharmacophore pattern seen in known actives). [37][38][39] By contrast, the above-mentioned pharmacophore-coloured ECFPs are genuine fragment counts. Apparently, pharmacophore multiplets and fragment counts seem to be conceptually different -in fact, they can be unified within the concept of "fuzzy" fragments, in which the nature of terminal fragment atoms is always explicit, while the nature of the intermediate, interconnecting atoms may be optionally mentioned or ignored.…”

Section: Introductionmentioning

confidence: 96%

ISIDA Property‐Labelled Fragment Descriptors

Ruggiu

Marcou

Varnek

et al. 2010

Molecular Informatics

125

145

View full text Add to dashboard Cite

ISIDA Property-Labelled Fragment Descriptors (IPLF) were introduced as a general framework to numerically encode molecular structures in chemoinformatics, as counts of specific subgraphs in which atom vertices are coloured with respect to some local property/feature. Combining various colouring strategies of the molecular graph - notably pH-dependent pharmacophore and electrostatic potential-based flagging - with several fragmentation schemes, the different subtypes of IPLFs may range from classical atom pair and sequence counts, to monitoring population levels of branched fragments or feature multiplets. The pH-dependent feature flagging, pursued at the level of each significantly populated microspecies involved in the proteolytic equilibrium, may furthermore add some competitive advantage over classical descriptors, even when the chosen fragmentation scheme is one of the state-of-the-art pattern extraction procedures (feature sequence or pair counts, etc.) in chemoinformatics. The implemented fragmentation schemes support counting (1) linear feature sequences, (2) feature pairs, (3) circular feature fragments a.k.a. "augmented atoms" or (4) feature trees. Fuzzy rendering - optionally allowing nonterminal fragment atoms to be counted as wildcards, ignoring their specific colours/features - ensures for a seamless transition between the "strict" counts (sequences or circular fragments) and the "fuzzy" multiplet counts (pairs or trees). Also, bond information may be represented or ignored, thus leaving the user a vast choice in terms of the level of resolution at which chemical information should be extracted into the descriptors. Selected IPLF subsets were - tree descriptors, in particular - successfully tested in both neighbourhood behaviour and QSAR modelling challenges, with very promising results. They showed excellent results in similarity-based virtual screening for analogue protease inhibitors, and generated highly predictive octanol-water partition coefficient and hERG channel inhibition models.

show abstract

Section: Introductionmentioning

confidence: 96%

ISIDA Property‐Labelled Fragment Descriptors

Ruggiu

Marcou

Varnek

et al. 2010

Molecular Informatics

125

145

View full text Add to dashboard Cite

show abstract

“…We also noted the numbers of distinct Murcko scaffolds in the active molecules that were retrieved, rather than just the number of active molecules. As recommended by Good et al [33], this was done to assess the effectiveness of the various weighting schemes for scaffold-hopping [41][42][43].…”

Section: Datasetsmentioning

confidence: 99%

Analysis and use of fragment-occurrence data in similarity-based virtual screening

Arif

Holliday

Willett

2009

J Comput Aided Mol Des

View full text Add to dashboard Cite

Current systems for similarity-based virtual screening use similarity measures in which all the fragments in a fingerprint contribute equally to the calculation of structural similarity. This paper discusses the weighting of fragments on the basis of their frequencies of occurrence in molecules. Extensive experiments with sets of active molecules from the MDL Drug Data Report and the World of Molecular Bioactivity databases, using fingerprints encoding Tripos holograms, Pipeline Pilot ECFC_4 circular substructures and Sunset Molecular keys, demonstrate clearly that frequency-based screening is generally more effective than conventional, unweighted screening. The results suggest that standardising the raw occurrence frequencies by taking the square root of the frequencies will maximise the effectiveness of virtual screening. An upper-bound analysis shows the complex interactions that can take place between representations, weighing schemes and similarity coefficients when similarity measures are computed, and provides a rationalisation of the relative performance of the various weighting schemes.

show abstract

“…The final step of the CATS descriptor calculation is the scaling of the vector [57,58]. The CATS descriptor was successfully employed in earlier de novo design projects and had proven useful for the purpose of scaffold-hopping [49,59,60].…”

Section: Scoring a Virtual Molecule By Topological Pharmacophoresmentioning

confidence: 99%

The concept of template-based de novo design from drug-derived molecular fragments and its application to TAR RNA

Schüller

Suhartono

Fechner

et al. 2007

J Comput Aided Mol Des

Self Cite

View full text Add to dashboard Cite

Principles of fragment-based molecular design are presented and discussed in the context of de novo drug design. The underlying idea is to dissect known drug molecules in fragments by straightforward pseudo-retro-synthesis. The resulting building blocks are then used for automated assembly of new molecules. A particular question has been whether this approach is actually able to perform scaffold-hopping. A prospective case study illustrates the usefulness of fragment-based de novo design for finding new scaffolds. We were able to identify a novel ligand disrupting the interaction between the Tat peptide and TAR RNA, which is part of the human immunodeficiency virus (HIV-1) mRNA. Using a single template structure (acetylpromazine) as reference molecule and a topological pharmacophore descriptor (CATS), new chemotypes were automatically generated by our de novo design software Flux. Flux features an evolutionary algorithm for fragment-based compound assembly and optimization. Pharmacophore superimposition and docking into the target RNA suggest perfect matching between the template molecule and the designed compound. Chemical synthesis was straightforward, and bioactivity of the designed molecule was confirmed in a FRET assay. This study demonstrates the practicability of de novo design to generating RNA ligands containing novel molecular scaffolds.

show abstract

Scaffold‐Hopping: How Far Can You Jump?

Cited by 139 publications

References 68 publications

ISIDA Property‐Labelled Fragment Descriptors

ISIDA Property‐Labelled Fragment Descriptors

Analysis and use of fragment-occurrence data in similarity-based virtual screening

The concept of template-based de novo design from drug-derived molecular fragments and its application to TAR RNA

Contact Info

Product

Resources

About