Escape from planarity in fragment-based drug discovery: A physicochemical and 3D property analysis of synthetic 3D fragment libraries

Hamilton, David J.; Dekker, Tom; Klein, Hanna F.; Janssen, Guido V.; O’Brien, Peter; Esch, Iwan J. P. de

doi:10.1016/j.ddtec.2021.05.001

Cited by 23 publications

(44 citation statements)

References 63 publications

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“…The theme of “3D fragment libraries” is also prominent, 102 following the realization that unexplored scaffolds represent a considerable opportunity. 88 Especially when developing new chemistries, it makes sense to screen the new scaffolds as fragments as this optimizes the chance of finding hits.…”

Section: Resultsmentioning

confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2020

Esch

Erlanson²,

Jahnke

et al. 2021

J. Med. Chem.

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Fragment-based drug discovery (FBDD) continues to evolve and make an impact in the pharmaceutical sciences. We summarize successful fragment-to-lead studies that were published in 2020. Having systematically analyzed annual scientific outputs since 2015, we discuss trends and best practices in terms of fragment libraries, target proteins, screening technologies, hit-optimization strategies, and the properties of hit fragments and the leads resulting from them. As well as the tabulated Fragment-to-Lead (F2L) programs, our 2020 literature review identifies several trends and innovations that promise to further increase the success of FBDD. These include developing structurally novel screening fragments, improving fragment-screening technologies, using new computer-aided design and virtual screening approaches, and combining FBDD with other innovative drug-discovery technologies.

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Section: Resultsmentioning

confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2020

Esch

Erlanson²,

Jahnke

et al. 2021

J. Med. Chem.

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show abstract

“…Both of these parameters are in fact known for being the more flexible parameters of those defined in the preceding section. [23,53,54] Scheme 2 shows the synthetic approaches toward the three classes. Amine fragments 10-11 were synthesised via indirect reductive amination [55] -first pre-forming the imine in dry MeOH, followed by reduction with NaBH 4 .…”

Section: Chemmedchemmentioning

confidence: 99%

“…[21] Within FBDD, in recent years there has been substantial interest in the design and synthesis of 3D fragments. [22,23] While the higher complexity of 3D fragments may reduce the chances of binding to a protein target, [16] the current scarcity of 3D fragments in screening collections might be a missed opportunity for FBDD. Often a limiting factor in FBDD, one crucial feature of any fragment hit is the ability to develop the molecule into a more potent lead molecule through the use of accessible growth vectors and associated chemistry.…”

Section: Introductionmentioning

confidence: 99%

“…[26] Indeed, in recent years various synthetic strategies have been deployed for the generation of 3D fragments, [26] producing appreciable diversity in both shape and physicochemical properties. [23] In 2014, Taylor et al [27] showed that of the ring systems present in FDA-approved drugs, the phenyl ring dominates the field, being almost ten times more prevalent than the second most utilised unit (pyridine). Fragments that contain these scaffolds have frequently been identified as hits and exploited in a significant number of successful fragment-to-lead campaigns.…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, we have shown that an isolated cyclobutane ring in synthetic 3D fragment libraries, if present, is most commonly used as a pendant aliphatic group or isostere of a geminal dimethyl unit and virtually never as a central scaffold. [23] In general, the strategy for cyclobutane inclusion in medicinal chemistry and FBDD appears to be that chemists tend to put 'a ring on a molecule' (as an aliphatic group), rather than 'a ring in a molecule' (as part of the framework).…”

Section: Introductionmentioning

confidence: 99%

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Puckering the Planar Landscape of Fragments: Design and Synthesis of a 3D Cyclobutane Fragment Library

et al. 2022

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Fragment-based drug discovery (FBDD) has a growing need for unique screening libraries. The cyclobutane moiety was identified as an underrepresented yet attractive three-dimensional (3D) scaffold. Synthetic strategies were developed via a key 3azido-cyclobutanone intermediate, giving potential access to a range of functional groups with accessible growth vectors. A focused set of 33 novel 3D cyclobutane fragments was synthesised, comprising three functionalities: secondary amines, amides, and sulfonamides. This library was designed using Principal Component Analysis (PCA) and an expanded version of the rule of three (RO3), followed by Principal Moment of Inertia (PMI) analysis to achieve both chemical diversity and high 3D character. Cis and trans ring isomers of library members were generated to maximise the shape diversity obtained, while limiting molecular complexity through avoiding enantiomers. Property analyses of the cyclobutane library indicated that it fares favourably against existing synthetic 3D fragment libraries in terms of shape and physicochemical properties.

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Diboron(4)‐Catalyzed Remote [3+2] Cycloaddition of Cyclopropanes via Dearomative/Rearomative Radical Transmission through Pyridine

Wang

Sun

et al. 2022

Angewandte Chemie

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Ring structures such as pyridine, cyclopentane or their combinations are important motifs in bioactive molecules. In contrast to previous cycloaddition reactions that necessitated a directly bonded initiating functional group, this work demonstrated a novel through‐(hetero)arene radical transmission concept for selective activation of a remote bond. An efficient, metal‐free and atom‐economical [3+2] cycloaddition between 4‐pyridinyl cyclopropanes and alkenes or alkynes has been developed for modular synthesis of pyridine‐substituted cyclopentanes, cyclopentenes and bicyclo[2.1.1]hexanes that are difficult to access using known methods. This complexity‐building reaction was catalyzed by a very simple and inexpensive diboron(4) compound and took place via dearomative/rearomative processes. The substrate scope was broad and more than 100 new compounds were prepared in generally high yields. Mechanistic experiments and density function theory (DFT) investigation supported a radical relay catalytic cycle involving alkylidene dihydropyridine radical intermediates and boronyl radical transfer.

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Escape from planarity in fragment-based drug discovery: A physicochemical and 3D property analysis of synthetic 3D fragment libraries

Cited by 23 publications

References 63 publications

Fragment-to-Lead Medicinal Chemistry Publications in 2020

Fragment-to-Lead Medicinal Chemistry Publications in 2020

Puckering the Planar Landscape of Fragments: Design and Synthesis of a 3D Cyclobutane Fragment Library

Diboron(4)‐Catalyzed Remote [3+2] Cycloaddition of Cyclopropanes via Dearomative/Rearomative Radical Transmission through Pyridine

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