Searching Fragment Spaces with Feature Trees

Lessel, Uta; Wellenzohn, Bernd; Lilienthal, Markus; Claußen, Holger

doi:10.1021/ci800272a

Cited by 85 publications

(72 citation statements)

References 26 publications

(28 reference statements)

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“…It is impractical to explicitly enumerate all these compounds and to search them, so methods have been developed to narrow down the search space, based on representing the molecules as combinations of feature trees. Lessel et al [33] have described further improvements to the Colibri approach. This universe can be searched very quickly using feature trees, and in a retrospective study, some known hits could be retrieved from a universe of 10 11 compounds with only 4 query structures as input.…”

Section: Discussionmentioning

confidence: 99%

IADE: a system for intelligent automatic design of bioisosteric analogs

Ertl

Lewis

2012

J Comput Aided Mol Des

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IADE, a software system supporting molecular modellers through the automatic design of non-classical bioisosteric analogs, scaffold hopping and fragment growing, is presented. The program combines sophisticated cheminformatics functionalities for constructing novel analogs and filtering them based on their drug-likeness and synthetic accessibility using automatic structure-based design capabilities: the best candidates are selected according to their similarity to the template ligand and to their interactions with the protein binding site. IADE works in an iterative manner, improving the fitness of designed molecules in every generation until structures with optimal properties are identified. The program frees molecular modellers from routine, repetitive tasks, allowing them to focus on analysis and evaluation of the automatically designed analogs, considerably enhancing their work efficiency as well as the area of chemical space that can be covered. The performance of IADE is illustrated through a case study of the design of a nonclassical bioisosteric analog of a farnesyltransferase inhibitor--an analog that has won a recent "Design a Molecule" competition.

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Section: Discussionmentioning

confidence: 99%

IADE: a system for intelligent automatic design of bioisosteric analogs

Ertl

Lewis

2012

J Comput Aided Mol Des

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“…The system has subsequently been applied using the Boehringer Ingelheim scaffold and approved reagent list (1600 scaffolds and 30 000 reagents, respectively) to generate a potential library of 5 Â 10 11 unique molecules, called BI CLAIM (Boehringer Ingelheim Comprehensive Library of Accessible Innovative Molecules) [15]. The system used the CoLibri software developed by BioSolveIT to encode the reaction schemes.…”

Section: Similarity Searching In Large Combinatorial Chemistry Spacesmentioning

confidence: 99%

Feature Trees

Brown

2013

Methods and Principles in Medicinal Chemistry

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“…The libraries are represented by building block databases and overall summary chemical reactions describing how the building blocks are combined to the final products. The search procedure matches first the building blocks and then checks whether they can be combined into a final molecule with one of the synthesis protocols 90,91. By overlay and alignment of several reduced graphs of known actives, a 2D query model for a set of known ligands can be generated, which can then be used for further queries 92,93…”

Section: Fragment Matching and Reduced Graphsmentioning

confidence: 99%

Computational methods for scaffold hopping

Schuffenhauer

2012

WIREs Comput Mol Sci

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It is not uncommon in drug discovery that the core fragment, typically called scaffold, of a molecule with an interesting biological activity cannot be developed further because of issues related to intellectual property, physicochemical properties, metabolic stability, or toxicity, to name only a few reasons. In this situation, it is desirable to replace this molecule with another having a different chemical connectivity, but similar shape and pharmacophore features enabling it to interact in the same way with the target as the original molecule. Such a replacement is called scaffold hopping. Several ligand-based virtual screening and scoring methods supporting the identification of novel ligands starting from known ligands and, if known, their bound conformation, are available. Scaffold hopping capability has been demonstrated for pharmacophore searches, fieldand shape-based similarity searches, alignment free similarity searches using three-dimensional (3D)-or connectivity-based descriptors, and fragment-based methods. Although for many methods successful prospective uses have been reported, rigorous systematic benchmarking of scaffold hopping is still challenging due to the lacking consensus in the definition of a scaffold. Despite their drawbacks, computational scaffold extraction methods have been frequently used in approximate benchmarks for scaffold hopping. In many systematic retrospective studies, connectivity-based methods were shown to be at least equally effective as 3D methods, especially when the conformations of the reference structures were generated with a conformer generator. However, in prospective comparison studies, especially when a hypothesis of the 3D binding conformation was available and used, often 3D methods were found to give superior results. C 2012 John Wiley & Sons, Ltd.

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Searching Fragment Spaces with Feature Trees

Cited by 85 publications

References 26 publications

IADE: a system for intelligent automatic design of bioisosteric analogs

IADE: a system for intelligent automatic design of bioisosteric analogs

Feature Trees

Computational methods for scaffold hopping

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