2021
DOI: 10.1126/sciadv.abd9307
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Multicomponent reaction–derived covalent inhibitor space

Abstract: The area of covalent inhibitors is gaining momentum due to recently introduced clinical drugs, but libraries of these compounds are scarce. Multicomponent reaction (MCR) chemistry is well known for its easy access to a very large and diverse chemical space. Here, we show that MCRs are highly suitable to generate libraries of electrophiles based on different scaffolds and three-dimensional shapes and highly compatible with multiple functional groups. According to the building block principle of MCR, acrylamide,… Show more

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Cited by 37 publications
(20 citation statements)
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“…[15] Thus we established a high yielding 3CLpro expression/purification system which allowed us to soak highly concentrated solutions of our herein and previously described electrophile libraries into preformed crystals in a high throughput mode. [23] The compounds were selected to represent diversity in scaffolds and electrophiles. A total of 181 different compounds were soaked.…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…[15] Thus we established a high yielding 3CLpro expression/purification system which allowed us to soak highly concentrated solutions of our herein and previously described electrophile libraries into preformed crystals in a high throughput mode. [23] The compounds were selected to represent diversity in scaffolds and electrophiles. A total of 181 different compounds were soaked.…”
Section: Resultsmentioning
confidence: 99%
“…They represent two classes of covalent inhibitors, the chloroacetamides and acrylic esters, both classes that have shown to be promising covalent inhibitors of multiple protein targets. [ 23 , 27 ] They bind in a variety of modes, mainly interacting with the S1′, S1 and S2 subsites, primarily making π‐π interactions with His41 and hydrophobic interactions with the sidechains of the S1′ site (Figure 6 A ). F3 was found to be non‐covalently bound to the 3Clpro, with its acrylamide warhead orientated away from the active Cys145.…”
Section: Resultsmentioning
confidence: 99%
“…The SARS‐CoV‐2 3CLpro is an attractive workhorse, not only because it is a covalent drug discovery target to combat COVID‐19, but also because of the uncomplicated access to large amounts of crystallization‐quality enzyme [15] . Thus we established a high yielding 3CLpro expression/purification system which allowed us to soak highly concentrated solutions of our herein and previously described electrophile libraries into preformed crystals in a high throughput mode [23] . The compounds were selected to represent diversity in scaffolds and electrophiles.…”
Section: Resultsmentioning
confidence: 99%
“…Four of the hits ( II‐G11 , II‐F10 , F1 , and F2 ) were found to be covalently bound to the active site Cys145 (Figure 6 B 1–4). They represent two classes of covalent inhibitors, the chloroacetamides and acrylic esters, both classes that have shown to be promising covalent inhibitors of multiple protein targets [23, 27] . They bind in a variety of modes, mainly interacting with the S1′, S1 and S2 subsites, primarily making π‐π interactions with His41 and hydrophobic interactions with the sidechains of the S1′ site (Figure 6 A).…”
Section: Resultsmentioning
confidence: 99%
“…Heterogeneous catalysts play a prominent role in the synthesis of fine chemicals through multicomponent reactions (MCRs) strategy. [65][66][67][68][69][70][71] Indeed, imidazole derivatives are an important category of heterocyclic compounds demonstrating biological properties and medicinal applications, which can be prepared using appropriate substrates through MCR strategy. 32,67,68,[72][73][74][75][76][77][78][79][80][81][82][83][84] This bunch of 1,3-diazoles exhibits therapeutic behaviors such as antibiotics, 85,86 antifungals, 87,88 and antagonistic activity.…”
Section: Introductionmentioning
confidence: 99%