Molecular docking-based virtual drug screening revealing an oxofluorenyl benzamide and a bromonaphthalene sulfonamido hydroxybenzoic acid as HDAC6 inhibitors with cytotoxicity against leukemia cells

Autoren

Mona Dawood
Mohamed Elbadawi
Madeleine Böckers
Gerhard Bringmann
Thomas Efferth

DOI

10.1016/j.biopha.2020.110454

ISSN

0753-3322

Zeitschrift

Biomedicine & Pharmacotherapy

Sprache

en

Artikelnummer

110454

Paginierung

110454 - 110454

Datum der Veröffentlichung

2020

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.biopha.2020.110454

Datum der Datenerfassung

2020

Titel

Molecular docking-based virtual drug screening revealing an oxofluorenyl benzamide and a bromonaphthalene sulfonamido hydroxybenzoic acid as HDAC6 inhibitors with cytotoxicity against leukemia cells

Ausgabe der Zeitschrift

129

Data source: Crossref

Abstract

HDAC6 is a crucial epigenetic modifier that plays a vital role in tumor progression and carcinogenesis due to its multiple biological functions. It is a unique member of class-II HDAC enzymes. It possesses two catalytic domains, which function independently of the overall enzyme activity. Up to date, there are only a few selective HDAC6 inhibitors with anti-cancer activity. In this study, 175,204 ligands obtained from the ZINC15 and OTAVAchemical databases were used for virtual drug screening against HDAC6. Molecular docking studies were performed for 100 selected compounds. Furthermore, the top 10 compounds obtained from docking were tested for their efficacy to inhibit the function of HDAC6. Five compounds (N-(9-oxo-9H-fluoren-3-yl)benzamide, 2-hydroxy-5-[(5-oxo-6-phenyl-4,5-dihydro-1,2,4-triazin-3-yl)amino]benzoic acid, 5-(4-bromonaphthalene-1-sulfonamido)-2-hydroxybenzoic acid, 2-(naphthalen-2-yl)-N-(1H-1,2,3,4-tetrazol-5-yl)cyclopropane-1-carboxamide, and 4-oxa-5,6 diazapentacyclo[10.7.1.0³,⁷.0⁸,²⁰.0¹⁴,¹⁹]icosa-1,3(7),5,8(20),9,11,14,16,18-nonaen-13-one) inhibited enzymatic activity by more than 50 % compared to DMSO as the control. Two candidates, (N-(9-oxo-9H-fluoren-3-yl)benzamide and 5-(4-bromonaphthalene-1-sulfonamido)-2-hydroxybenzoic acid), were identified with considerable cytotoxicity towards drug-sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. Microscale thermophoresis revealed the binding of N-(9-oxo-9H-fluoren-3-yl)benzamide and 5-(4-bromonaphthalene-1-sulfonamido)-2-hydroxybenzoic acid to purified HDAC6 protein. Both compounds induced apoptosis in a dose-dependent manner as analyzed by flow cytometry. In conclusion, we demonstrate for the first time that these two compounds bind to HDAC6, inhibit its function, and exert cytotoxic activity by apoptosis induction.

Addresses

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.

Autoren

Mona Dawood
Mohamed Elbadawi
Madeleine Böckers
Gerhard Bringmann
Thomas Efferth

DOI

10.1016/j.biopha.2020.110454

eISSN

1950-6007

Externe Identifier

PubMed Identifier: 32768947

Funding acknowledgements

Deutsche Forschungsgemeinschaft: GRK 2015/2

Open access

false

ISSN

0753-3322

Zeitschrift

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

Schlüsselwörter

Cell Line, Tumor
Humans
Leukemia
Benzamides
Naphthalenes
Drug Resistance, Multiple
Apoptosis
Molecular Structure
Structure-Activity Relationship
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Drug Discovery
Histone Deacetylase Inhibitors
Hydroxybenzoates
Databases, Chemical
Molecular Docking Simulation
Histone Deacetylase 6

Sprache

eng

Medium

Print-Electronic

Online publication date

2020

Paginierung

110454

Datum der Veröffentlichung

2020

Status

Published

Publisher licence

CC BY-NC-ND

Datum der Datenerfassung

2020

Titel

Molecular docking-based virtual drug screening revealing an oxofluorenyl benzamide and a bromonaphthalene sulfonamido hydroxybenzoic acid as HDAC6 inhibitors with cytotoxicity against leukemia cells.

Sub types

Journal Article

Ausgabe der Zeitschrift

129

Data source: Europe PubMed Central

Abstract

HDAC6 is a crucial epigenetic modifier that plays a vital role in tumor progression and carcinogenesis due to its multiple biological functions. It is a unique member of class-II HDAC enzymes. It possesses two catalytic domains, which function independently of the overall enzyme activity. Up to date, there are only a few selective HDAC6 inhibitors with anti-cancer activity. In this study, 175,204 ligands obtained from the ZINC15 and OTAVAchemical databases were used for virtual drug screening against HDAC6. Molecular docking studies were performed for 100 selected compounds. Furthermore, the top 10 compounds obtained from docking were tested for their efficacy to inhibit the function of HDAC6. Five compounds (N-(9-oxo-9H-fluoren-3-yl)benzamide, 2-hydroxy-5-[(5-oxo-6-phenyl-4,5-dihydro-1,2,4-triazin-3-yl)amino]benzoic acid, 5-(4-bromonaphthalene-1-sulfonamido)-2-hydroxybenzoic acid, 2-(naphthalen-2-yl)-N-(1H-1,2,3,4-tetrazol-5-yl)cyclopropane-1-carboxamide, and 4-oxa-5,6 diazapentacyclo[10.7.1.0³,⁷.0⁸,²⁰.0¹⁴,¹⁹]icosa-1,3(7),5,8(20),9,11,14,16,18-nonaen-13-one) inhibited enzymatic activity by more than 50 % compared to DMSO as the control. Two candidates, (N-(9-oxo-9H-fluoren-3-yl)benzamide and 5-(4-bromonaphthalene-1-sulfonamido)-2-hydroxybenzoic acid), were identified with considerable cytotoxicity towards drug-sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. Microscale thermophoresis revealed the binding of N-(9-oxo-9H-fluoren-3-yl)benzamide and 5-(4-bromonaphthalene-1-sulfonamido)-2-hydroxybenzoic acid to purified HDAC6 protein. Both compounds induced apoptosis in a dose-dependent manner as analyzed by flow cytometry. In conclusion, we demonstrate for the first time that these two compounds bind to HDAC6, inhibit its function, and exert cytotoxic activity by apoptosis induction.

Date of acceptance

2020

Autoren

Mona Dawood
Mohamed Elbadawi
Madeleine Böckers
Gerhard Bringmann
Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/32768947

DOI

10.1016/j.biopha.2020.110454

eISSN

1950-6007

Zeitschrift

Biomed Pharmacother

Schlüsselwörter

Cancer
Drug development
Epigenetics
HDAC6
Microscale thermophoresis
Virtual drug screening
Apoptosis
Benzamides
Cell Line, Tumor
Databases, Chemical
Dose-Response Relationship, Drug
Drug Discovery
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Histone Deacetylase 6
Histone Deacetylase Inhibitors
Humans
Hydroxybenzoates
Leukemia
Molecular Docking Simulation
Molecular Structure
Naphthalenes
Structure-Activity Relationship

Sprache

eng

Country

France

Paginierung

110454

PII

S0753-3322(20)30647-8

Datum der Veröffentlichung

2020

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2021

Titel

Molecular docking-based virtual drug screening revealing an oxofluorenyl benzamide and a bromonaphthalene sulfonamido hydroxybenzoic acid as HDAC6 inhibitors with cytotoxicity against leukemia cells.

Sub types

Journal Article

Ausgabe der Zeitschrift

129

Data source: PubMed

Molecular docking-based virtual drug screening revealing an oxofluorenyl benzamide and a bromonaphthalene sulfonamido hydroxybenzoic acid as HDAC6 inhibitors with cytotoxicity against leukemia cells

Tools