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An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M^pro inhibitor.

ABSTRACT: Designing covalent inhibitors is increasingly important, although it remains challenging. Here, we present covalentizer, a computational pipeline for identifying irreversible inhibitors based on structures of targets with non-covalent binders. Through covalent docking of tailored focused libraries, we identify candidates that can bind covalently to a nearby cysteine while preserving the interactions of the original molecule. We found ∼11,000 cysteines proximal to a ligand across 8,386 complexes in the PDB. Of these, the protocol identified 1,553 structures with covalent predictions. In a prospective evaluation, five out of nine predicted covalent kinase inhibitors showed half-maximal inhibitory concentration (IC₅₀) values between 155 nM and 4.5 μM. Application against an existing SARS-CoV M^pro reversible inhibitor led to an acrylamide inhibitor series with low micromolar IC₅₀ values against SARS-CoV-2 M^pro. The docking was validated by 12 co-crystal structures. Together these examples hint at the vast number of covalent inhibitors accessible through our protocol.

SUBMITTER: Zaidman D

PROVIDER: S-EPMC8228784 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M<sup>pro</sup> inhibitor.

Zaidman Daniel D Gehrtz Paul P Filep Mihajlo M Fearon Daren D Gabizon Ronen R Douangamath Alice A Prilusky Jaime J Duberstein Shirly S Cohen Galit G Owen C David CD Resnick Efrat E Strain-Damerell Claire C Lukacik Petra P Barr Haim H Walsh Martin A MA von Delft Frank F London Nir N

Cell chemical biology 20210625 12

Designing covalent inhibitors is increasingly important, although it remains challenging. Here, we present covalentizer, a computational pipeline for identifying irreversible inhibitors based on structures of targets with non-covalent binders. Through covalent docking of tailored focused libraries, we identify candidates that can bind covalently to a nearby cysteine while preserving the interactions of the original molecule. We found ∼11,000 cysteines proximal to a ligand across 8,386 complexes ...[more]

PMID: 34174194

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Project description:A series of derivatives (5-14) were synthesized through the diazotization of sulfadiazine with active methylene compounds. The chemical structures of these newly designed compounds were validated through spectral and elemental analysis techniques. The antiproliferative potential of derivatives 5-14 was assessed against three distinct cancer cell lines (A431, A549, and H1975) using the MTT assay. The results revealed that compounds 8, 12, and 14 exhibited the most potent antiproliferative activity, with IC50 values ranging from 2.31 to 7.56 μM. Notably, these values were significantly lower than those of known EGFR inhibitors, including erlotinib, gefitinib, and osimertinib, suggesting the potential of these derivatives as novel antiproliferative agents. Furthermore, compound 12 was identified as the most potent inhibitor of both EGFRWT and EGFRT790M protein kinases, with IC50 values of 14.5 and 35.4 nM, respectively. These results outperformed those of gefitinib and osimertinib, which exhibited IC50 values of 18.2 and 368.2 nM, and 57.8 and 8.5 nM, respectively. Molecular docking studies of compounds 8, 12, and 14 within the ATP-binding sites of both EGFRWT and EGFRT790M corroborated the in vitro results when compared to erlotinib, gefitinib, and osimertinib. The docking results indicated that compound 8 exhibited a favorable binding affinity for both EGFRWT and EGFRT790M, with binding scores of -6.40 kcal mol-1 and -7.53 kcal mol-1, respectively, which were comparable to those of gefitinib and osimertinib, with binding scores of -8.01 and -8.72 kcal mol-1, respectively. Furthermore, an assessment of the most promising EGFR inhibitors (8, 12, and 14) using the egg-boiled method for their in silico ADME properties revealed significant lipophilicity, blood-brain barrier (BBB) penetration, and gastrointestinal (GIT) absorption. Collectively, our designed analogs, particularly compounds 8, 12, and 14, exhibit promising dual antiproliferative and EGFRWT and EGFRT790M kinase inhibitory properties, positioning them as efficient candidates for further therapeutic development.

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An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M^pro inhibitor.

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An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M<sup>pro</sup> inhibitor.

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An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mpro inhibitor.

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An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M&lt;sup&gt;pro&lt;/sup&gt; inhibitor.

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OmicsDI is part of the ELIXIR infrastructure

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An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M^pro inhibitor.

An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M<sup>pro</sup> inhibitor.