Identification of the Inhibitory Compounds for Metallo-β-lactamases and Structural Analysis of the Binding Modes

Kamo, Taichi; Kuroda, K.; Kondo, Shota; Hayashi, U.; Fudo, Satoshi; Yoneda, Tomohiro; Takaya, Akiko; Nukaga, Michiyoshi; Hoshino, Tyuji

doi:10.1248/cpb.c21-00611

Cited by 3 publications

(9 citation statements)

References 28 publications

(28 reference statements)

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“…Compound 1 was identified by an in vitro screening in our previous work. 23 A collection of in-house compounds was utilized for the screening. The collection contains the compounds inhibiting RNase H activity of HIV-1 reverse transcriptase 29−33 and endo-nuclease activity of the influenza polymerase acidic subunit.…”

Section: Resultsmentioning

confidence: 99%

“…Expression and purification of MBLs were performed similarly to a previous study. 23 An Escherichia coli, Rosetta 2, was transformed with the plasmid vector coding IMP-1 or NDM-1. The recombinant IMP-1 or NDM-1 was expressed as a 6 × Hisfused Trx-tag-conjugated form.…”

Section: Virtual Modification Of Compoundsmentioning

confidence: 99%

“…The X-ray diffraction results were acquired by the synchrotron light source of the Photon-Factory at KEK, Japan. Atom coordinates were determined by the molecular replacement method, using a crystal structure of PDB code 6JKA 23 as a search model.…”

Section: Assay Of Inhibitory Activitymentioning

confidence: 99%

“…In our previous study, we identified compound 1, which showed inhibitory activity against IMP-1 and NDM-1. 23 The cocrystal structural analysis of compound 1 and IMP-1 suggested that compound 1 interacted with two zinc ions at the active center, with the δ-lactam ring cleaved by the enzymatic function of MBL. In this work, we synthesized and evaluated dozens of derivatives of compound 1, utilizing a computational design and an X-ray crystal analysis.…”

Section: Introductionmentioning

confidence: 99%

“…In our previous study, we identified compound 1 , which showed inhibitory activity against IMP-1 and NDM-1 . The cocrystal structural analysis of compound 1 and IMP-1 suggested that compound 1 interacted with two zinc ions at the active center, with the δ-lactam ring cleaved by the enzymatic function of MBL.…”

Section: Introductionmentioning

confidence: 99%

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Development of Inhibitory Compounds for Metallo-beta-lactamase through Computational Design and Crystallographic Analysis

Kamo,

Kuroda,

Nimura

et al. 2024

Biochemistry

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Metallo-β-lactamases (MBL) deactivate β-lactam antibiotics through a catalytic reaction caused by two zinc ions at the active center. Since MBLs deteriorate a wide range of antibiotics, they are dangerous factors for bacterial multidrug resistance. In this work, organic synthesis, computational design, and crystal structure analysis were performed to obtain potent MBL inhibitors based on a previously identified hit compound. The hit compound comprised 3,4-dihydro-2(1H)-quinolinone linked with a phenyl-ether-methyl group via a thiazole ring. In the first step, the thiazole ring was replaced with a tertiary amine to avoid the planar structure. In the second step, we virtually modified the compound by keeping the quinolinone backbone. Every modified compound was bound to a kind of MBL, imipenemase-1 (IMP-1), and the binding pose was optimized by a molecular mechanics calculation. The binding scores were evaluated for the respective optimized binding poses. Given the predicted binding poses and calculated binding scores, candidate compounds were determined for organic syntheses. The inhibitory activities of the synthesized compounds were measured by an in vitro assay for two kinds of MBLs, IMP-1 and New Delhi metallo-β-lactamase (NDM-1). A quinolinone connected with an amine bound with methylphenyl-ether-propyl and cyclohexyl-ethyl showed a 50% inhibitory concentration of 4.8 μM. An X-ray crystal analysis clarified the binding structure of a synthesized compound to IMP-1. The δ-lactam ring of quinolinone was hydrolyzed, and the generated carboxyl group was coordinated with zinc ions. The findings on the chemical structure and binding pose are expected to be a base for developing MBL inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Virtual Modification Of Compoundsmentioning

confidence: 99%

Section: Assay Of Inhibitory Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development of Inhibitory Compounds for Metallo-beta-lactamase through Computational Design and Crystallographic Analysis

Kamo,

Kuroda,

Nimura

et al. 2024

Biochemistry

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Computational Screening of Inhibitory Compounds for SARS-Cov-2 3CL Protease with a Database Consisting of Approved and Investigational Chemicals

Miwa

Guo

Hata

et al. 2023

CHEMICAL & PHARMACEUTICAL BULLETIN

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Computational screening is one of the fundamental techniques in drug discovery. Each compound in a chemical database is bound to the target protein in virtual, and candidate compounds are selected from the binding scores. In this work, we carried out combinational computation of docking simulation to generate binding poses and molecular mechanics calculation to estimate binding scores. The coronavirus infectious disease has spread worldwide, and effective chemotherapy is strongly required. The viral 3-chymotrypsinlike (3CL) protease is a good target of low molecular-weight inhibitors. Hence, computational screening was performed to search for inhibitory compounds acting on the 3CL protease. As a preliminary assessment of the performance of this approach, we used 51 compounds for which inhibitory activity had already been confirmed. Docking simulations and molecular mechanics calculations were performed to evaluate binding scores. The preliminary evaluation suggested that our approach successfully selected the inhibitory compounds identified by the experiments. The same approach was applied to 8820 compounds in a database consisting of approved and investigational chemicals. Hence, docking simulations, molecular mechanics calculations, and re-evaluation of binding scores including solvation effects were performed, and the top 200 poses were selected as candidates for experimental assays. Consequently, 25 compounds were chosen for in vitro measurement of the enzymatic inhibitory activity. From the enzymatic assay, 5 compounds were identified to have inhibitory activities against the 3CL protease. The present work demonstrated the feasibility of a combination of docking simulation and molecular mechanics calculation for practical use in computational virtual screening.

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<i>In Silico</i> Identification of Inhibitory Compounds for SARS-Cov-2 Papain-Like Protease

Miwa,

Guo,

Hata

et al. 2023

CHEMICAL & PHARMACEUTICAL BULLETIN

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Virtual screening with high-performance computers is a powerful and cost-effective technique in drug discovery. A chemical database is searched to find candidate compounds firmly bound to a target protein, judging from the binding poses and/or binding scores. The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infectious disease has spread worldwide for the last three years, causing severe slumps in economic and social activities. SARS-Cov-2 has two viral proteases: 3-chymotrypsin-like (3CL) and papain-like (PL) protease. While approved drugs have already been released for the 3CL protease, no approved agent is available for PL protease. In this work, we carried out in silico screening for the PL protease inhibitors, combining docking simulation and molecular mechanics calculation. Docking simulations were applied to 8,820 molecules in a chemical database of approved and investigational compounds. Based on the binding poses generated by the docking simulations, molecular mechanics calculations were performed to optimize the binding structures and to obtain the binding scores. Based on the binding scores, 57 compounds were selected for in vitro assay of the inhibitory activity. Five inhibitory compounds were identified from the in vitro measurement. The predicted binding structures of the identified five compounds were examined, and the significant interaction between the individual compound and the protease catalytic site was clarified. This work demonstrates that computational virtual screening by combining docking simulation with molecular mechanics calculation is effective for searching candidate compounds in drug discovery.

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Identification of the Inhibitory Compounds for Metallo-β-lactamases and Structural Analysis of the Binding Modes

Cited by 3 publications

References 28 publications

Development of Inhibitory Compounds for Metallo-beta-lactamase through Computational Design and Crystallographic Analysis

Development of Inhibitory Compounds for Metallo-beta-lactamase through Computational Design and Crystallographic Analysis

Computational Screening of Inhibitory Compounds for SARS-Cov-2 3CL Protease with a Database Consisting of Approved and Investigational Chemicals

<i>In Silico</i> Identification of Inhibitory Compounds for SARS-Cov-2 Papain-Like Protease

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