New leads of metallo-beta-lactamase inhibitors from structure-based pharmacophore design

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

New leads of metallo-beta-lactamase inhibitors from structure-based pharmacophore design. / Olsen, Lars; Jost, Sandra; Adolph, Hans-Werner; Pettersson, Ingrid; Hemmingsen, Lars; Jørgensen, Flemming Steen.

In: Bioorganic & Medicinal Chemistry, Vol. 14, No. 8, 2006, p. 2627-2635.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Olsen, L, Jost, S, Adolph, H-W, Pettersson, I, Hemmingsen, L & Jørgensen, FS 2006, 'New leads of metallo-beta-lactamase inhibitors from structure-based pharmacophore design', Bioorganic & Medicinal Chemistry, vol. 14, no. 8, pp. 2627-2635. https://doi.org/10.1016/j.bmc.2005.11.046

APA

Olsen, L., Jost, S., Adolph, H-W., Pettersson, I., Hemmingsen, L., & Jørgensen, F. S. (2006). New leads of metallo-beta-lactamase inhibitors from structure-based pharmacophore design. Bioorganic & Medicinal Chemistry, 14(8), 2627-2635. https://doi.org/10.1016/j.bmc.2005.11.046

Vancouver

Olsen L, Jost S, Adolph H-W, Pettersson I, Hemmingsen L, Jørgensen FS. New leads of metallo-beta-lactamase inhibitors from structure-based pharmacophore design. Bioorganic & Medicinal Chemistry. 2006;14(8):2627-2635. https://doi.org/10.1016/j.bmc.2005.11.046

Author

Olsen, Lars ; Jost, Sandra ; Adolph, Hans-Werner ; Pettersson, Ingrid ; Hemmingsen, Lars ; Jørgensen, Flemming Steen. / New leads of metallo-beta-lactamase inhibitors from structure-based pharmacophore design. In: Bioorganic & Medicinal Chemistry. 2006 ; Vol. 14, No. 8. pp. 2627-2635.

Bibtex

@article{fddbb4d0a1c011ddb6ae000ea68e967b,
title = "New leads of metallo-beta-lactamase inhibitors from structure-based pharmacophore design",
abstract = "We have applied pharmacophore generation, database searching, docking methodologies, and experimental enzyme kinetics to discover new structures for design of di-zinc metallo-beta-lactamase inhibitors. Based on crystal structures of class B1 metallo-beta-lactamases with a succinic acid and a mercapto-carboxylic acid inhibitor bound to the enzyme, two pharmacophore models were constructed. With the Catalyst program, these pharmacophores were used to search the ACD database, which provided a total of 74 hits representing four different chemical classes of compounds: Dicarboxylic acids, phosphonic and sulfonic acid derivatives, and mercapto-carboxylic acids. All hits were docked into different metallo-beta-lactamases (from classes B1 and B3) using the GOLD docking program. A selection scheme based on the GOLD scores, the Catalyst fit and shape values, and the size of the compounds (molecular weight, surface area, and number of rotatable bonds) was developed and thirteen compounds representing all four chemical classes were selected for experimental studies. Three compounds with new scaffolds hitherto not present in metallo-beta-lactamase inhibitors have IC50 values less than 15 microM and may serve as starting points in the design of metallo-beta-lactamase inhibitors.",
keywords = "Enzyme Inhibitors, Models, Molecular, Multivariate Analysis, beta-Lactamases",
author = "Lars Olsen and Sandra Jost and Hans-Werner Adolph and Ingrid Pettersson and Lars Hemmingsen and J{\o}rgensen, {Flemming Steen}",
year = "2006",
doi = "10.1016/j.bmc.2005.11.046",
language = "English",
volume = "14",
pages = "2627--2635",
journal = "Bioorganic & Medicinal Chemistry",
issn = "0968-0896",
publisher = "Pergamon Press",
number = "8",

}

RIS

TY - JOUR

T1 - New leads of metallo-beta-lactamase inhibitors from structure-based pharmacophore design

AU - Olsen, Lars

AU - Jost, Sandra

AU - Adolph, Hans-Werner

AU - Pettersson, Ingrid

AU - Hemmingsen, Lars

AU - Jørgensen, Flemming Steen

PY - 2006

Y1 - 2006

N2 - We have applied pharmacophore generation, database searching, docking methodologies, and experimental enzyme kinetics to discover new structures for design of di-zinc metallo-beta-lactamase inhibitors. Based on crystal structures of class B1 metallo-beta-lactamases with a succinic acid and a mercapto-carboxylic acid inhibitor bound to the enzyme, two pharmacophore models were constructed. With the Catalyst program, these pharmacophores were used to search the ACD database, which provided a total of 74 hits representing four different chemical classes of compounds: Dicarboxylic acids, phosphonic and sulfonic acid derivatives, and mercapto-carboxylic acids. All hits were docked into different metallo-beta-lactamases (from classes B1 and B3) using the GOLD docking program. A selection scheme based on the GOLD scores, the Catalyst fit and shape values, and the size of the compounds (molecular weight, surface area, and number of rotatable bonds) was developed and thirteen compounds representing all four chemical classes were selected for experimental studies. Three compounds with new scaffolds hitherto not present in metallo-beta-lactamase inhibitors have IC50 values less than 15 microM and may serve as starting points in the design of metallo-beta-lactamase inhibitors.

AB - We have applied pharmacophore generation, database searching, docking methodologies, and experimental enzyme kinetics to discover new structures for design of di-zinc metallo-beta-lactamase inhibitors. Based on crystal structures of class B1 metallo-beta-lactamases with a succinic acid and a mercapto-carboxylic acid inhibitor bound to the enzyme, two pharmacophore models were constructed. With the Catalyst program, these pharmacophores were used to search the ACD database, which provided a total of 74 hits representing four different chemical classes of compounds: Dicarboxylic acids, phosphonic and sulfonic acid derivatives, and mercapto-carboxylic acids. All hits were docked into different metallo-beta-lactamases (from classes B1 and B3) using the GOLD docking program. A selection scheme based on the GOLD scores, the Catalyst fit and shape values, and the size of the compounds (molecular weight, surface area, and number of rotatable bonds) was developed and thirteen compounds representing all four chemical classes were selected for experimental studies. Three compounds with new scaffolds hitherto not present in metallo-beta-lactamase inhibitors have IC50 values less than 15 microM and may serve as starting points in the design of metallo-beta-lactamase inhibitors.

KW - Enzyme Inhibitors

KW - Models, Molecular

KW - Multivariate Analysis

KW - beta-Lactamases

U2 - 10.1016/j.bmc.2005.11.046

DO - 10.1016/j.bmc.2005.11.046

M3 - Journal article

C2 - 16378729

VL - 14

SP - 2627

EP - 2635

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

IS - 8

ER -

ID: 8029943