Discovery of a novel indole pharmacophore for the irreversible inhibition of myeloperoxidase (MPO)

Patnaik, Anup; Axford, Laura; Deng, Lin; Cohick, Evan; Ren, Xianglin; Loi, Sally; Kecman, Sam; Hollis-Symynkywicz, Micah; Harrison, Tyler; Papillon, Julien P. N.; Dales, Natalie A.; Hamann, Lawrence G.; Lee, Lac; Regard, Jean B.; Marcinkeviciene, Jovita; Marro, M.; Patterson, Andrew W.

doi:10.1016/j.bmc.2020.115548

Cited by 10 publications

(7 citation statements)

References 39 publications

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“…Nonetheless, no significant improvements in yield were observed. This poor outcome is in line with other literature precedents, where only a scarce number of examples for N-arylation of substituted azaindoles with typically low yields are reported. , The poor outcome of the reaction can be explained by the deactivating nature of the substituents and “trapping” effect of the neighboring nitrogen of the pyridine unit. Subsequent Suzuki couplings required K 2 CO 3 /Pd(dppf)Cl 2 or NaHCO 3 /Pd(PPh 3 ) 4 catalytic systems depending on the nature of the employed boron species.…”

Section: Results and Discussionsupporting

confidence: 89%

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From Pyrazolones to Azaindoles: Evolution of Active-Site SHP2 Inhibitors Based on Scaffold Hopping and Bioisosteric Replacement

et al. 2020

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The tyrosine phosphatase SHP2 controls the activity of pivotal signaling pathways, including MAPK, JAK-STAT, and PI3K-Akt. Aberrant SHP2 activity leads to uncontrolled cell proliferation, tumorigenesis, and metastasis. SHP2 signaling was recently linked to drug resistance against cancer medications such as MEK and BRAF inhibitors. In this work, we present the development of a novel class of azaindole SHP2 inhibitors. We applied scaffold hopping and bioisosteric replacement concepts to eliminate unwanted structural motifs and to improve the inhibitor characteristics of the previously reported pyrazolone SHP2 inhibitors. The most potent azaindole 45 inhibits SHP2 with an IC 50 = 0.031 μM in an enzymatic assay and with an IC 50 = 2.6 μM in human pancreas cells (HPAF-II). Evaluation in a series of cellular assays for metastasis and drug resistance demonstrated efficient SHP2 blockade. Finally, 45 inhibited proliferation of two cancer cell lines that are resistant to cancer drugs and diminished ERK signaling.

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Section: Results and Discussionsupporting

confidence: 89%

“…1 H NMR (300 MHz, CDCl 3 ): δ 8.39−8.32 (m, 1H), 7.94−7.88 (m, 1H), 7.56−7.47 (m, 3H), 7.08−7.00 (d, J = 8.9 Hz, 2H), 3.87 (s, 3H). 13 (56). NaH (60% in oil, 84 mg, 1.36 mmol) was added to a stirred solution of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (400 mg, 1.24 mmol, 1 equiv) in DMF (50 mL) at 0 °C.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

From Pyrazolones to Azaindoles: Evolution of Active-Site SHP2 Inhibitors Based on Scaffold Hopping and Bioisosteric Replacement

et al. 2020

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“…27 Because the inhibitory effect of these compounds upon MPO has already been established, they were not included for testing against the enzyme as it would overestimate the success rate of the virtual screening methodology. The recent described MPO inhibitors aminopyridines and a new indole scaffold matched with the MPO inhibitor-like profile in all parameters (Table S2), 66,67 despite the fact that they were not included in the MPO inhibitor-like rule elaboration. Together, these data corroborate the accuracy of the MPO inhibitor-like rule to discover new MPO inhibitors.…”

Section: Structure-basedmentioning

confidence: 94%

Integration of an Inhibitor-like Rule and Structure-based Virtual Screening for the Discovery of Novel Myeloperoxidase Inhibitors

Matos

Júnior

Meotti

2020

J. Chem. Inf. Model.

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Myeloperoxidase (MPO) is an attractive therapeutic target against inflammation. Herein, we developed an inhibitor-like rule, based on known MPO inhibitors, and generated a target database containing 6546 molecules with privileged inhibitory properties. Using a structure-based approach validated by decoys, robust statistical metrics, redocking, and cross-docking, we selected 10 putative MPO inhibitors with high chemical diversity. At 20 μM, six of these 10 compounds (i.e., 60% success rate) inhibited more than 20% of the chlorinating activity of the enzyme. Additionally, we found that compound ZINC9089086 forms hydrogen bonds with Arg233 and with the hemic carboxylate. It makes a π-stacking interaction with the heme group and displays a high affinity for the enzyme active site. When incubated with purified MPO, ZINC9089086 inhibited the chlorinating activity of the enzyme with an IC50 of 2.2 ± 0.1 μM in a reversible manner. Subsequent experiments revealed that ZINC9089086 inhibited hypochlorous acid production in dHL-60 cells and human neutrophils. Furthermore, the theoretical ADME/Tox profile indicated that this compound exhibits low toxicity risks and adequate pharmacokinetic parameters, thus making ZINC9089086 a very promising candidate for preclinical anti-inflammatory studies. Overall, our study shows that integrating an inhibitor-like rule with a validated structure-based methodology is an excellent approach for improving the success rate and molecular diversity of novel MPO inhibitors with good pharmacokinetics and toxicological profiles. By combining these tools, it was possible to increase the assurance rate, which ultimately diminishes the costs and time needed for the acquisition, synthesis, and evaluation of new compounds.

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“…The recently synthesized small molecule drug for MPO inhibition in clinical trials, Verdiperstat, is produced by AstraZeneca and Biohaven Pharmaceuticals. Mild adverse effects including nausea, headache, and insomnia have been linked to verdiperstat. , Therefore, the appending of a brand-new medication for MPO inhibition that has fewer negative effects is urgently needed. The present study focuses on the synthesis and application of phytochemical-based organic scaffolds targeting cardiovascular disease risk factors, namely, diabetes and atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Structural Elucidation, In Silico and In Vitro Studies of New Class of Methylenedioxyphenyl-Based Amide Derivatives as Potential Myeloperoxidase Inhibitors for Cardiovascular Protection

Rajan,

Karthikeyan,

Desikan

2024

ACS Omega

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Novel methylenedioxyphenyl-based amides, especially N-(4-methoxybenzyl)-6-nitrobenzo-[1,3]-dioxole-5-carboxamide (MDC) and N-(3-acetylphenyl)-6-nitrobenzo-[1,3]-dioxole-5-carboxamide (ADC), potential cardiovascular preventive agents, are successfully synthesized, and their chemical structures are verified by 1 H and 13 C NMR, Fourier transform infrared (FT-IR), high-resolution mass spectrometry (HRMS), and single-crystal Xray diffraction (SC-XRD) analyses. Data obtained from SC-XRD reveal that MDC and ADC are both monoclinic molecules with Z = 2 and 4, respectively. From density functional theory (DFT) calculations, 3.54 and 3.96 eV are the energy gaps of the optimized MDC and ADC structures, respectively. MDC and ADC exhibit an electrophilicity index value of more than 1.5 eV, suggesting that they can act as an electrophile, facilitating bond formation with biomolecules. Hirshfeld surface analysis demonstrates that more than 25% of atomic interactions in both MDC and ADC are from H•••H interactions. Based on pharmacokinetic predictions, MDC and ADC exhibit drug-like properties, and molecular docking simulations revealed favorable interactions with active site pockets. Both MDC and ADC achieved higher docking scores of −7.74 and −7.79 kcal/mol, respectively, with myeloperoxidase (MPO) protein. From docking results, MPO was found to be most favorable followed by dipeptidyl peptidase-4 (DPP-4) and α-glucosidase (α-GD). Antioxidant, anti-inflammatory, and in vitro enzymatic studies of MDC and ADC indicate that MDC is more selective toward MPO and more potent than ADC. The application of MDC to inhibit myeloperoxidase could be ascertained to reduce the cardiovascular risk factor. This can be supported from the results of computational docking (based on hydrogen bonding and docking score), in vitro antioxidant and anti-inflammatory properties, and MPO enzymatic inhibition (based on the percentage of inhibition and IC 50 values).

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Discovery of a novel indole pharmacophore for the irreversible inhibition of myeloperoxidase (MPO)

Cited by 10 publications

References 39 publications

From Pyrazolones to Azaindoles: Evolution of Active-Site SHP2 Inhibitors Based on Scaffold Hopping and Bioisosteric Replacement

From Pyrazolones to Azaindoles: Evolution of Active-Site SHP2 Inhibitors Based on Scaffold Hopping and Bioisosteric Replacement

Integration of an Inhibitor-like Rule and Structure-based Virtual Screening for the Discovery of Novel Myeloperoxidase Inhibitors

Synthesis, Structural Elucidation, In Silico and In Vitro Studies of New Class of Methylenedioxyphenyl-Based Amide Derivatives as Potential Myeloperoxidase Inhibitors for Cardiovascular Protection

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