Applications of “linkers” in fragment-based drug design

Wu, Xin; Zhang, Yuan; Liu, Songbin; Liu, Chang; Tang, Guotao; Xuan, Chuang; Lei, Xiaoyong; Peng, Junmei

doi:10.1016/j.bioorg.2022.105921

Cited by 8 publications

(22 citation statements)

References 163 publications

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“…Interestingly, we do not observe significant differences in the length of the fragments, which is often a key route to linker optimization (Figure S4). 5,8 However, we observe alternative binding conformations within the allosteric pocket for the active 2 versus inactive 1 best matches the parent allosteric inhibitors 8-9 (Figure 1D & S4). This supports the notion that ideal linkers must retain the original interactions for the original proteinfragment-interactions, and indicates that the more hydrophobic fragment (allosteric site) is more tolerant to alterations in binding mode.…”

mentioning

confidence: 70%

“…[4][5][6] For fragment linking, where two fragments are chemically coupled to form a single compound, the desired outcome is the production of a substantially higher affinity molecule, otherwise known as superadditivity. 7,8 Despite the straightforwardness of this approach, connecting fragments with a well-optimized linker in practice has proven to be a considerable challenge. 5,[9][10][11] Fragment linker design criteria that maximize chances of success have been proposed previously, 4,5 but little is known about how certain linkers can improve or impair a compound's potency.…”

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confidence: 99%

“…Chemical structures of bivalent ATP-allosteric inhibitors consisting of N-linked reversible (1) as well as C-linked reversible (2,3) and covalent (4) scaffolds. Parent ATP site imidazole reversible (5-6) and covalent(7) inhibitors as well as dibenzodiazepinone allosteric inhibitors(8)(9).…”

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confidence: 99%

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Examining molecular factors of inactive versus active bivalent EGFR inhibitors: A missing link in fragment-based drug design.

Wittlinger

Ogboo

Pham

et al. 2023

Preprint

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The optimization of linkers that connect fragments within drug binding sites represents an impediment in fragment-based drug discovery (FBDD). To improve our understand of the molecular factors that enable effective fragment linking, we have produced a series of compounds that bind to the ATP and allosteric sites of the EGFR kinase domain connected by two distinct linker structures. We find the linker is responsible for opposing impacts on potency against EGFR mutants, the most potent of which are active in human cancer cells. Comparison of X-ray cocrystal structures of active versus inactive molecules provide unique experimentally derived insights into linker design criteria such as how fragment flexibility and intermolecular interactions can serve compound design broadly in drug optimization.

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confidence: 70%

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confidence: 99%

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Examining molecular factors of inactive versus active bivalent EGFR inhibitors: A missing link in fragment-based drug design.

Wittlinger

Ogboo

Pham

et al. 2023

Preprint

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“… 20 In this regard, isosteric replacement of the trimethylene linker in FOS with a nitrogen‐containing linker provides opportunities for developing new FOS analogs that may possess favorable activities. In fact, the design and optimization of linkers has become a critical strategy in drug development in recent years, which makes it possible to control the stability and solubility of compounds, enhance drug targeting and bioavailability, and reduce the toxicity and side effects of active molecules 21,22 …”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of fosmidomycin analogs containing aza‐linkers and their biological activity evaluation

Wu,

Bu,

Yang

et al. 2023

Pest Management Science

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BackgroundThe enzymes involved in the MEP pathway are attractive targets of new mode of action for developing anti‐infective drugs and herbicides, and the inhibitors against IspC, the second key enzyme in the pathway, have been intensively investigated, however, few works are reported regarding the IspC inhibitors designed for new herbicide discovery.ResultsA series of fosmidomycin (FOS) analogs with nitrogen‐containing linkers replacing the trimethylene linker between the two active substructures of FOS, phosphonic acid and hydroxamic acid, were designed, and the synthesis was carried out by a facile three‐step route of sequential aza‐Michael addition of α‐amino acids to dibenzyl vinylphosphonate, amidation of the amino acid carboxyl with O‐benzyl hydroxylamine, and simultaneous removal of the benzyl protective groups. Biological activity evaluation on IspC and model plants revealed that some compounds had moderate enzyme and model plant growth inhibition effects, but in particular, compound 10g that has a N‐(4‐fluorophenylethyl) nitrogen‐containing linker exhibited the best plant inhibition activities, superior to the control FOS against the model plants Arabidopsis thaliana, Brassica napus L., Amaranthus retroflexus, and Echinochloa crus‐galli. The dimethylallyl pyrophosphate rescue assay on Arabidopsis thaliana validated that both 10g and FOS exert their herbicidal activity by blocking the MEP pathway, a result consistent with the molecular docking that confirmed 10g and FOS binding to the IspC active site in a similar way.ConclusionCompound 10g has excellent herbicidal activity and represents the first herbicide lead structure of new mode of action that targets IspC enzyme in the MEP pathway.This article is protected by copyright. All rights reserved.

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“…[26,27] The hybrids can be classified as directly linked hybrids, spacer-linked hybrids, fused hybrids and merged hybrids, based on the mode of connecting the two involved molecules and the type of connection have direct impact on the bioactivity, pharmacokinetics and pharmacodynamics. [28,29] This strategy has been widely used for designing new entities for anti-cancer therapy. [30] The synthesis and anti-cancer evaluation of molecular hybrids containing the DHPM nucleus has also been reported in the literature, including the DHPM-semicarbazone hybrids, described as antiproliferative and apoptosis inducers in human hepatocyte carcinoma cells (HepG2) through inhibition of human DNA ligase 1 .…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative Effect and Autophagy Inhibition of Dihydropyrimidinone‐Cinnamic Acid Hybrids

et al. 2022

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Here we report the design, synthesis and evaluation of dihydropyrimidinones (DHPMs)‐cinnamic acids hybrids as potential anti‐cancer compounds. The synthetic route was successfully performed and the products obtained in good to excellent yields. These compounds were tested against LNCaP and PC‐3 metastatic prostate cancer cells and RWPE‐1 prostate cells. The results indicate that hybridization was effective, since the hybrids were much more cytotoxic than DHPMs and cinnamic acids evaluated separately. Compound 3 a was the most potent hybrid against PC‐3 cells (IC50 of 15.7 μM) and LNCaP cells (IC50 of 11.5 μM) and was further optimized by bioisosterism and molecular simplification strategies leading to three new analogues (5, 7 and 8). Compounds 3 a, 7 and 8 showed an antiproliferative effect against PC‐3 cells without inducing cell death nor cell cycle arrest. The mechanism of action of compound 8 was further investigated. The results indicated that compound 8 inhibits autophagic flux, and this effect could be linked to the antiproliferative activity. Moreover, in silico prediction of some molecular properties related to pharmacokinetics showed that all the hybrids meet the criteria for a drug prototype to have a good absorption and permeation for oral administration. These results highlight the potential use of DHPMs‐cinnamic acids hybrids as antiproliferative agents for further evaluation of the antitumor activity in vivo.

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Applications of “linkers” in fragment-based drug design

Cited by 8 publications

References 163 publications

Examining molecular factors of inactive versus active bivalent EGFR inhibitors: A missing link in fragment-based drug design.

Examining molecular factors of inactive versus active bivalent EGFR inhibitors: A missing link in fragment-based drug design.

Design and synthesis of fosmidomycin analogs containing aza‐linkers and their biological activity evaluation

Antiproliferative Effect and Autophagy Inhibition of Dihydropyrimidinone‐Cinnamic Acid Hybrids

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