“Scaffold-Hopping” by Topological Pharmacophore Search: A Contribution to Virtual Screening

Schneider, Gisbert; Neidhart, Werner; Giller, Thomas; Schmid, Gerard M.

doi:10.1002/(sici)1521-3773(19991004)38:19<2894::aid-anie2894>3.3.co;2-6

Cited by 44 publications

(53 citation statements)

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“…The fitness of a designed molecule was computed by means of a weighted sum of Euclidian distances to reference ligands in the chemical space spanned by the CATS descriptor (17)(18)(19). This molecular representation belongs to the class of correlation-vector descriptors and was conceived for the purpose of 'scaffold-hopping,' that is, the identification of isofunctional but structurally different chemotypes.…”

Section: Fitness Functionmentioning

confidence: 99%

“…Vector entries were scaled by the number of non-hydrogen atoms. CATS has been shown to be sufficiently fast and suitable for de novo design purposes in previous applications (17)(18)(19). The primary reason for choosing this descriptor was to enable scaffoldhopping during the design process.…”

Section: Fitness Functionmentioning

confidence: 99%

“…In the proposed computer-aided approach, this is performed by a ligand similarity-based fitness function. Similarity is measured by computing the average distance of a candidate structure to a set of known reference molecules in the space of a topological atom-pair descriptor [chemically advanced template search (CATS) descriptor, see Data and Methods section] (17)(18)(19). Gained knowledge is then incorporated in the process of choosing building blocks and linkers in subsequent design steps.…”

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confidence: 99%

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Concept of Combinatorial De Novo Design of Drug‐like Molecules by Particle Swarm Optimization

et al. 2008

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We present a fast stochastic optimization algorithm for fragment-based molecular de novo design (COLIBREE, Combinatorial Library Breeding). The search strategy is based on a discrete version of particle swarm optimization. Molecules are represented by a scaffold, which remains constant during optimization, and variable linkers and side chains. Different linkers represent virtual chemical reactions. Side-chain building blocks were obtained from pseudo-retrosynthetic dissection of large compound databases. Here, ligand-based design was performed using chemically advanced template search (CATS) topological pharmacophore similarity to reference ligands as fitness function. A weighting scheme was included for particle swarm optimization-based molecular design, which permits the use of many reference ligands and allows for positive and negative design to be performed simultaneously. In a case study, the approach was applied to the de novo design of potential peroxisome proliferator-activated receptor subtype-selective agonists. The results demonstrate the ability of the technique to cope with large combinatorial chemistry spaces and its applicability to focused library design. The technique was able to perform exploitation of a known scheme and at the same time explorative search for novel ligands within the framework of a given molecular core structure. It thereby represents a practical solution for compound screening in the early hit and lead finding phase of a drug discovery project.

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Section: Fitness Functionmentioning

confidence: 99%

Section: Fitness Functionmentioning

confidence: 99%

mentioning

confidence: 99%

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Concept of Combinatorial De Novo Design of Drug‐like Molecules by Particle Swarm Optimization

et al. 2008

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“…), (ii) identification of new classes of active chemotypes [e.g. scaffold hopping (18,19)], (iii) identification of privileged substructures (20,21), and (iv) exploration of chemotypes strongly associated with inactives [e.g. data shaving (6)].…”

Section: Chemotype-enrichment Plotsmentioning

confidence: 99%

Hierarchical Strategy for Identifying Active Chemotype Classes in Compound Databases

2006

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A general methodology is presented for analyzing patterns of activity in compound databases, which is based on the use of structural chemotypes and provides a focused, hierarchical classification of active compounds. Each node in the hierarchical tree corresponds to a specific chemotype and is labeled by a unique code or identifier. All chemotypes at a given level of the hierarchy define equivalence classes, and those of higher structural resolution have a strict parent-child (i.e. subset) relationship to those of lower resolution. Active chemotypes contain a relatively high proportion of actives and are characterized through the use of enrichment plots. These plots show the relationship of occupancy to activity enrichment for a set of chemotypes at a given level of structural resolution. Paths through the hierarchy from chemotypes of lower to those of higher structural resolution (e.g. reduced cyclic system skeletons --> cyclic system skeletons --> cyclic systems --> complete molecules) are unique. Unique paths in the hierarchy that only pass through active chemotypes are called chains or paths of actives. These chains provide links for identifying structurally related active compounds at increasing levels of structural resolution. Analysis of actives can also be carried out at any specific level of structural resolution deemed appropriate by the investigator. Chemotype codes can be used to search compound databases for new molecules possessing these codes or sets of hierarchically related codes. An example, based on the NCI AIDS database, is presented that illustrates the general approach and provides a more detailed description of several interesting classes of active chemotypes and their inter-relationships.

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“…In this study, we extend the concept of fingerprint hybridization, develop novel hybrid fingerprints from other fingerprint types, and create hybrid fingerprints specifically for the purpose of 'scaffold hopping' (18), i.e. the identification of active compounds having different core structures.…”

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Reduction and Recombination of Fingerprints of Different Design Increase Compound Recall and the Structural Diversity of Hits

Nisius

Bajorath

2010

Chem Biol Drug Des

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We report an advanced 'hybrid fingerprint' design concept specifically for the purpose of scaffold hopping. The generation of hybrid fingerprints includes two major steps. In the 'fingerprint reduction' step, bit positions of different types of fingerprints (e.g. substructural and pharmacophore fingerprints) are ranked according to their statistical significance and ability to discriminate between specifically active compounds and database decoys. On the basis of bit ranking, subsets containing the most discriminatory bit positions are determined. In the subsequent 'fingerprint recombination' step, bit subsets from different fingerprints are combined to yield a new compound class-directed fingerprint representation for similarity searching. Here, we generate hybrids from multiple fingerprints and analyze their search performance in comparison with parental fingerprints on compound activity classes that exclusively consist of molecules with unique core structures and that exhibit different levels of intra-class structural diversity. Fingerprint reduction is found to be a critical component of hybrid design. The resulting compound class-directed hybrid fingerprints further increase the similarity search performance and scaffold hopping potential of their parental fingerprints. Thus, fingerprint reduction and recombination improve compound recall and increase the structural diversity of hits.Key words: compound class-directed similarity searching, fingerprint recombination, fingerprint reduction, Kullback-Leibler divergence, scaffold hopping Similarity searching using two-dimensional (2D) molecular fingerprints is a widely applied technique in pharmaceutical research for computational screening of large compounds databases (1-3). Binary keyed fingerprints are bit-string representations of molecular structure and properties where each bit encodes the presence or absence of a specific chemical feature. Diverse types of fingerprints have been introduced that encode molecular information in different ways, for example, as substructures, topological pathways, pharmacophore patterns, or numerical property descriptors (2). Most conventional fingerprint designs have a fixed length, but molecule-or compound classspecific fingerprints of variable format have also been introduced (4,5). A systematic comparison of standard fingerprints capturing different aspects of molecular structure has recently been reported (6).Regardless of fingerprint design, conventional similarity searching relies on the use of complete fingerprint representations as descriptors and on the quantification of fingerprint overlap as a measure of molecular similarity (1). However, in recent years, modifications to standard fingerprint searching have been reported that include consensus fingerprints (7), bit scaling (8), or reverse fingerprinting (9).Furthermore, concepts for the generation of minimal fingerprint representations retaining high search performance have recently also been introduced. These methods include bit density reduction (10), bit silen...

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“Scaffold-Hopping” by Topological Pharmacophore Search: A Contribution to Virtual Screening

Cited by 44 publications

References 3 publications

Concept of Combinatorial De Novo Design of Drug‐like Molecules by Particle Swarm Optimization

Concept of Combinatorial De Novo Design of Drug‐like Molecules by Particle Swarm Optimization

Hierarchical Strategy for Identifying Active Chemotype Classes in Compound Databases

Reduction and Recombination of Fingerprints of Different Design Increase Compound Recall and the Structural Diversity of Hits

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