Covalent binders in drug discovery

Vasudevan, Anil; Argiriadi, M.A.; Baranczak, Aleksandra; Friedman, Michael; Gavrilyuk, Julia; Hobson, Adrian D.; Hulce, Jonathan J.; Osman, Sami; Wilson, Noel S.

doi:10.1016/bs.pmch.2018.12.002

Cited by 37 publications

(29 citation statements)

References 173 publications

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“…As no host-cell proteases are currently known with this specificity, early drug discovery was directed towards the so-called covalent Michael inhibitors [10], via electrophilic attack to the cysteinyl residue. On the other hand, the consensus in drug discovery leads to excluding electrophiles from drug candidates for reasons relating to safety and adverse effects such as allergies, tissue destruction, or carcinogenesis [11].…”

mentioning

confidence: 99%

Identification of potential binders of the main protease 3CLpro of the COVID-19 via structure-based ligand design and molecular modeling

Macchiagodena

Pagliai

Procacci

2020

Chemical Physics Letters

165

158

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A B S T R A C TWe have applied a computational strategy, using a combination of virtual screening, docking and molecular dynamics techniques, aimed at identifying possible lead compounds for the non-covalent inhibition of the main protease 3CL pro of the SARS-CoV2 Coronavirus. Based on the X-ray structure (PDB code: 6LU7), ligands were generated using a multimodal structure-based design and then docked to the monomer in the active state. Docking calculations show that ligand-binding is strikingly similar in SARS-CoV and SARS-CoV2 main proteases. The most potent docked ligands are found to share a common binding pattern with aromatic moieties connected by rotatable bonds in a pseudo-linear arrangement.

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confidence: 99%

Identification of potential binders of the main protease 3CLpro of the COVID-19 via structure-based ligand design and molecular modeling

Macchiagodena

Pagliai

Procacci

2020

Chemical Physics Letters

165

158

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“…The term “calicheamicins” designates a family of enediyne antitumor antibiotics isolated from the fermentation broth of Micromonospora echinospora. They exert their action by binding DNA in the minor groove and triggering DNA strand scission [ 111 , 112 ]. They show a potent antitumor activity, being suitable candidates as ADC payloads.…”

Section: Adcs For Ovarian Cancermentioning

confidence: 99%

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

2021

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In the last decade, antibody-drug conjugates (ADCs), normally formed by a humanized antibody and a small drug via a chemical cleavable or non-cleavable linker, have emerged as a potential treatment strategy in cancer disease. They allow to get a selective delivery of the chemotherapeutic agents at the tumor level, and, consequently, to improve the antitumor efficacy and, especially to decrease chemotherapy-related toxicity. Currently, nine antibody-drug conjugate-based formulations have been already approved and more than 80 are under clinical trials for the treatment of several tumors, especially breast cancer, lymphomas, and multiple myeloma. To date, no ADCs have been approved for the treatment of gynecological formulations, but many formulations have been developed and have reached the clinical stage, especially for the treatment of ovarian cancer, an aggressive disease with a low five-year survival rate. This manuscript analyzes the ADCs formulations that are under clinical research in the treatment of gynecological carcinomas, specifically ovarian, endometrial, and cervical tumors.

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“…and methionine (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). There are more than 50 covalent FDA-approved drugs, and most react at amino acids other than cysteine, such as penicillin, which uses a β-lactam reactive group to form a covalent bond with a serine residue of the penicillin-binding protein target (42), and the oncology drug bortezomib, which uses a boronic acid warhead to react at a threonine residue on the proteasome (43).…”

Section: Significancementioning

confidence: 99%

Small-molecule covalent bond formation at tyrosine creates a binding site and inhibits activation of Ral GTPases

Bum‐Erdene

Liu

González-Gutiérrez

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Ral (Ras-like) GTPases are directly activated by oncogenic Ras GTPases. Mutant K-Ras (G12C) has enabled the development of covalent K-Ras inhibitors currently in clinical trials. However, Ral, and the overwhelming majority of mutant oncogenic K-Ras, are devoid of a druggable pocket and lack an accessible cysteine for the development of a covalent inhibitor. Here, we report that covalent bond formation by an aryl sulfonyl fluoride electrophile at a tyrosine residue (Tyr-82) inhibits guanine exchange factor Rgl2-mediated nucleotide exchange of Ral GTPase. A high-resolution 1.18-Å X-ray cocrystal structure shows that the compound binds to a well-defined binding site in RalA as a result of a switch II loop conformational change. The structure, along with additional high-resolution crystal structures of several analogs in complex with RalA, confirm the importance of key hydrogen bond anchors between compound sulfone oxygen atoms and Ral backbone nitrogen atoms. Our discovery of a pocket with features found on known druggable sites and covalent modification of a bystander tyrosine residue present in Ral and Ras GTPases provide a strategy that could lead to therapeutic agent targeting oncogenic Ras mutants that are devoid of a cysteine nucleophile.

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Covalent binders in drug discovery

Cited by 37 publications

References 173 publications

Identification of potential binders of the main protease 3CLpro of the COVID-19 via structure-based ligand design and molecular modeling

Identification of potential binders of the main protease 3CLpro of the COVID-19 via structure-based ligand design and molecular modeling

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

Small-molecule covalent bond formation at tyrosine creates a binding site and inhibits activation of Ral GTPases

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