Increased building block access through collaboration

Helal, Christopher J.; Bartolozzi, Alessandra; Goble, Steven D.; Mani, Neelakanda S.; Guzmán-Pérez, Angel; Ohri, Ajay K.; Shi, Zhicai; Subramanyam, Chakrapani

doi:10.1016/j.drudis.2018.03.001

Cited by 9 publications

(7 citation statements)

References 13 publications

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“…[18] Instead, they come from building blocksreagents that are used to introduce chemical diversity into a fixed-core lead structure (or novelty for scaffold hopping) and essential in modulating the overall pharmacological properties of drug candidates. [19] In early 2000s, synthesis of building blocks became an important part of the industry, [20] and to date, many pharmaceutical companies have invested millions of dollars in establishing internal chemical stores of building blocks, and various business models were developed to ensure their accessibility. [21] Recently, AstraZeneca scientists proposed the key features of building blocks relevant to medicinal chemistry: the presence of a functional group with manageable chemical reactivity, as well as compliance of the fragment that is incorporated into the synthesized molecule with the so-called mnemonic 'Rule of 2'.…”

Section: Introductionmentioning

confidence: 99%

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

2021

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Current medicinal chemistry relies heavily on the quality of building blocks, i. e. reagents used to introduce chemical diversity into the target molecules. The last decade witnessed an emergence of many novel (or well-overlooked old) chemotypes for drug discovery, which is related to adapting new synthetic methodologies, designing new sp 3 -enriched bioisosteres, paying attention to previously underrated (or even unwanted) structural motifs, or combination thereof. In this review with 532 references, a survey of selected chemotypes that emerged recently in medicinal chemistry is provided, with a focus on the synthesis of the corresponding building blocks. Thus, saturated (hetero)aliphatic boronates, sulfonyl fluorides, sulfinates, non-classical sp 3 -enriched benzene isosteres, bicyclic morpholine/piperidine/piperazine analogs, as well as gemdifluorinated cycloalkanes (as an example of emerging fluorinated motifs) are discussed.

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Section: Introductionmentioning

confidence: 99%

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

2021

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“…For building blocks, they are a class of reagents used to introduce chemical diversity into a fixed-core lead structure, which can be divided into four parts: core, linker, substituent groups, and molecular scaffold . Appropriate building blocks support the synthesis of molecules with desirable structural attributes and physiochemical properties . In this section, we mainly discuss the property-based rules, which provide adequate and consistent description of the important properties for drug-like molecules, such as MW, log P , N HBA , N HBD , etc .…”

Section: Drug-likeness Filtersmentioning

confidence: 99%

Application of Negative Design To Design a More Desirable Virtual Screening Library

Yang

Lü

et al. 2020

J. Med. Chem.

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Negative design is a group of virtual screening methods that aims at weeding out compounds with undesired properties during the early stages of drug development. These methods are mainly designed to predict three important types of pharmacological properties: drug-likeness, frequent hitters, and toxicity. In order to achieve high screening efficiency, most negative design methods are physicochemical property-based and/or substructure-based rules or filters. Such methods have advantages of simplicity and good interpretability, but they also suffer from some defects such as inflexibility, discontinuity, and hard decisionmaking. In this review, the advances in negative design for the evaluations of druglikeness, frequent hitters, and toxicity are outlined. In addition, the related Web servers and software packages developed recently for negative design are summarized. Finally, future research directions in this field are discussed.

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“…[6][7][8][9] Alongside this, there is now a recognition that the availability of 'high quality' building blocks is pivotal to the construction of compound screening collections that will deliver both good success rates in high-throughput screening and 'high quality' hits for development into potential drug candidates. [10][11][12] In this context, as part of AstraZeneca's 'strategic reagent initiative', Goldberg et al have parametrised building block quality in the form of a 'rule of 2' for key metrics: MW < 200, clogP < 2, hydrogen bond donor count (HBD) £ 2 and hydrogen bond acceptor count (HBA) £ 4. 10 building blocks that are equipped with cross-coupling potential -this is a key design feature of 3D building block 1.…”

Section: Introductionmentioning

confidence: 99%