Advanced approaches of developing targeted covalent drugs

Gai, Conghao; Harnor, Suzannah J.; Zhang, Shihao; Cano, Céline; Zhuang, Chunlin; Zhao, Qing

doi:10.1039/d2md00216g

Cited by 9 publications

(10 citation statements)

References 136 publications

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“…The Goldscore suggested the possibility of carbonyl replacement to covalently bind to Cys145. The mechanism for the reaction of this carbonyl as an aldehyde group covalently bound with cysteine residue was previously described 43 , 44 . Their interactions to the amino acids in the binding pocket were also similar to the interactions found with PF-07321332.…”

Section: Resultsmentioning

confidence: 99%

Structural analysis of the coronavirus main protease for the design of pan-variant inhibitors

Rungruangmaitree

Phoochaijaroen

Chimprasit

et al. 2023

Sci Rep

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With the rapid rate of SARS-CoV-2 Main protease (Mpro) structures deposition, a computational method that can combine all the useful structural features becomes crucial. This research focuses on the frequently occurring atoms and residues to find a generalized strategy for inhibitor design given a large amount of protein complexes from SARS-CoV in contrast to SARS-CoV-2 Mpro. By superposing large numbers of the ligands onto the protein template and grid box, we can analyse which part of the structure is conserved from position-specific interaction for both data sets for the development of pan-Mpro antiviral design. The difference in conserved recognition sites from the crystal structures can be used to determine specificity determining residues for designing selective drugs. We can display pictures of the imaginary shape of the ligand by unionising all atoms from the ligand. We also pinpoint the most probable atom adjustments to imitate the frequently found densities from the ligand atoms statistics. With molecular docking, Molecular Dynamics simulation, and MM-PBSA methods, a carbonyl replacement at the nitrile warhead (N5) of Paxlovid’s Nirmatrelvir (PF-07321332) was suggested. By gaining insights into the selectivity and promiscuity regions for proteins and ligands, crucial residues are highlighted, and the antiviral design strategies are proposed.

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Section: Resultsmentioning

confidence: 99%

Structural analysis of the coronavirus main protease for the design of pan-variant inhibitors

Rungruangmaitree

Phoochaijaroen

Chimprasit

et al. 2023

Sci Rep

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“…Considering the intrinsic reactivity of the 2-chloroacetamide electrophilic warhead in compound 6 , there are concerns about the risk of nonspecific covalent binding. − In order to identify a safer covalent ZAP-70 inhibitor for in vivo use, we have replaced the 2-chloroacetamide in 6 with an acrylamide ( 7 ), which is commonly used as a mildly reactive warhead in approved covalent kinase drugs . We then evaluated these compounds for their chemical reactivity toward thiol using the glutathione (GSH) incubation assay, which included the covalent kinase drug afatinib as a control. , This result revealed that compound 7 exhibited higher stability when incubated with GSH, with a half-life of 254 min, compared to 6 ( t 1/2 = 54 min) and afatinib ( t 1/2 = 66 min), suggesting that compound 7 may have reduced chemical reactivity toward nonspecific targets (Supporting information, Table S1).…”

Section: Resultsmentioning

confidence: 99%

Discovery and Structural Optimization of Covalent ZAP-70 Kinase Inhibitors against Psoriasis

Rao,

Yang,

Feng

et al. 2023

J. Med. Chem.

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Psoriasis is a chronic inflammatory skin disease closely related with T cells, and its management remains a challenge. Novel targets and associated drugs are urgently needed. Zeta-chain-associated protein kinase 70 kDa (ZAP-70) has been recognized as a potential target for treating autoimmune diseases due to its crucial role in T cell receptor signaling. In our previous work, we identified a potent and selective covalent ZAP-70 inhibitor with anti-inflammatory activity in vitro. Herein, we report the structural optimization of covalent ZAP-70 inhibitors. Our efforts led to the discovery of compound 25 (RDN2150), which exhibited potent inhibitory activity against ZAP-70 and favorable selectivity. It also demonstrated promising inhibitory effects on T cell activation and inflammatory cytokine production. Furthermore, a topical application of 25 resulted in significant efficacy in an imiquimod-induced psoriasis mouse model. Overall, these findings present the basis of a promising strategy for the treatment of psoriasis by targeting ZAP-70.

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“…In recent years, the development of targeted covalent inhibitors has gained popularity worldwide. These inhibitors involve specific groups known as electrophilic warheads, which form irreversible bonds with nucleophilic amino acid residues in biological targets, such as proteins [ 283 ].…”

Section: Role Of Electrophilic Compounds In Diseasesmentioning

confidence: 99%

Electrophilic Compounds in the Human Diet and Their Role in the Induction of the Transcription Factor NRF2

Andrés,

Pérez de la Lastra,

Bustamante Munguira

et al. 2024

IJMS

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The phrase “Let food be thy medicine…” means that food can be a form of medicine and medicine can be a form of food; in other words, that the diet we eat can have a significant impact on our health and well-being. Today, this phrase is gaining prominence as more and more scientific evidence suggests that one’s diet can help prevent and treat disease. A diet rich in fruits, vegetables, whole grains, and lean protein can help reduce the risk of heart disease, cancer, diabetes, and other health problems and, on the other hand, a diet rich in processed foods, added sugars, and saturated fats can increase the risk of the same diseases. Electrophilic compounds in the diet can have a significant impact on our health, and they are molecules that covalently modify cysteine residues present in the thiol-rich Keap1 protein. These compounds bind to Keap1 and activate NRF2, which promotes its translocation to the nucleus and its binding to DNA in the ARE region, triggering the antioxidant response and protecting against oxidative stress. These compounds include polyphenols and flavonoids that are nucleophilic but are converted to electrophilic quinones by metabolic enzymes such as polyphenol oxidases (PPOs) and sulfur compounds present in foods such as the Brassica genus (broccoli, cauliflower, cabbage, Brussel sprouts, etc.) and garlic. This review summarizes our current knowledge on this subject.

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Advanced approaches of developing targeted covalent drugs

Abstract: This review highlights developing strategies of covalent drug discovery and successful applications to address challenges of designing effective covalent drugs.

Cited by 9 publications

References 136 publications

Structural analysis of the coronavirus main protease for the design of pan-variant inhibitors

Structural analysis of the coronavirus main protease for the design of pan-variant inhibitors

Discovery and Structural Optimization of Covalent ZAP-70 Kinase Inhibitors against Psoriasis

Electrophilic Compounds in the Human Diet and Their Role in the Induction of the Transcription Factor NRF2

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