Computational screening of fatty acid synthase inhibitors against thioesterase domain

© 2017 Informa UK Limited, trading as Taylor & Francis Group Thioesterase (TE) domain of fatty acid synthase (FAS) is an attractive therapeutic target for design and development of anticancer drugs. In this present work, we search for the potential FAS inhibitors of TE domain from the ZINC dat...

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Main Authors: Wanwisa Panman, Bodee Nutho, Supakarn Chamni, Supaporn Dokmaisrijan, Nawee Kungwan, Thanyada Rungrotmongkol
Format: Journal
Published: 2018
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http://cmuir.cmu.ac.th/jspui/handle/6653943832/43422
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spelling th-cmuir.6653943832-434222018-04-25T07:34:36Z Computational screening of fatty acid synthase inhibitors against thioesterase domain Wanwisa Panman Bodee Nutho Supakarn Chamni Supaporn Dokmaisrijan Nawee Kungwan Thanyada Rungrotmongkol Biochemistry, Genetics and Molecular Biology Agricultural and Biological Sciences Arts and Humanities © 2017 Informa UK Limited, trading as Taylor & Francis Group Thioesterase (TE) domain of fatty acid synthase (FAS) is an attractive therapeutic target for design and development of anticancer drugs. In this present work, we search for the potential FAS inhibitors of TE domain from the ZINC database based on similarity search using three natural compounds as templates, including flavonoids, terpenoids, and phenylpropanoids. Molecular docking was used to predict the interaction energy of each screened ligand compared to the reference compound, which is methyl γ-linolenylfluorophosphonate (MGLFP). Based on this computational technique, rosmarinic acid and its eight analogs were observed as a new series of potential FAS inhibitors, which showed a stronger binding affinity than MGLFP. Afterward, nine docked complexes were studied by molecular dynamics simulations for investigating protein–ligand interactions and binding free energies using MM-PB(GB)SA, MM-3DRISM-KH, and QM/MM-GBSA methods. The binding free energy calculation indicated that the ZINC85948835 (R34) displayed the strongest binding efficiency against the TE domain of FAS. There are eight residues (S2308, I2250, E2251, Y2347, Y2351, F2370, L2427, and E2431) mainly contributed for the R34 binding. Moreover, R34 could directly form hydrogen bonds with S2308, which is one of the catalytic triad of TE domain. Therefore, our finding suggested that R34 could be a potential candidate as a novel FAS-TE inhibitor for further drug design. 2018-01-24T03:45:40Z 2018-01-24T03:45:40Z 2017-12-07 Journal 15380254 07391102 2-s2.0-85038030583 10.1080/07391102.2017.1408496 https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85038030583&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/43422
institution Chiang Mai University
building Chiang Mai University Library
country Thailand
collection CMU Intellectual Repository
topic Biochemistry, Genetics and Molecular Biology
Agricultural and Biological Sciences
Arts and Humanities
spellingShingle Biochemistry, Genetics and Molecular Biology
Agricultural and Biological Sciences
Arts and Humanities
Wanwisa Panman
Bodee Nutho
Supakarn Chamni
Supaporn Dokmaisrijan
Nawee Kungwan
Thanyada Rungrotmongkol
Computational screening of fatty acid synthase inhibitors against thioesterase domain
description © 2017 Informa UK Limited, trading as Taylor & Francis Group Thioesterase (TE) domain of fatty acid synthase (FAS) is an attractive therapeutic target for design and development of anticancer drugs. In this present work, we search for the potential FAS inhibitors of TE domain from the ZINC database based on similarity search using three natural compounds as templates, including flavonoids, terpenoids, and phenylpropanoids. Molecular docking was used to predict the interaction energy of each screened ligand compared to the reference compound, which is methyl γ-linolenylfluorophosphonate (MGLFP). Based on this computational technique, rosmarinic acid and its eight analogs were observed as a new series of potential FAS inhibitors, which showed a stronger binding affinity than MGLFP. Afterward, nine docked complexes were studied by molecular dynamics simulations for investigating protein–ligand interactions and binding free energies using MM-PB(GB)SA, MM-3DRISM-KH, and QM/MM-GBSA methods. The binding free energy calculation indicated that the ZINC85948835 (R34) displayed the strongest binding efficiency against the TE domain of FAS. There are eight residues (S2308, I2250, E2251, Y2347, Y2351, F2370, L2427, and E2431) mainly contributed for the R34 binding. Moreover, R34 could directly form hydrogen bonds with S2308, which is one of the catalytic triad of TE domain. Therefore, our finding suggested that R34 could be a potential candidate as a novel FAS-TE inhibitor for further drug design.
format Journal
author Wanwisa Panman
Bodee Nutho
Supakarn Chamni
Supaporn Dokmaisrijan
Nawee Kungwan
Thanyada Rungrotmongkol
author_facet Wanwisa Panman
Bodee Nutho
Supakarn Chamni
Supaporn Dokmaisrijan
Nawee Kungwan
Thanyada Rungrotmongkol
author_sort Wanwisa Panman
title Computational screening of fatty acid synthase inhibitors against thioesterase domain
title_short Computational screening of fatty acid synthase inhibitors against thioesterase domain
title_full Computational screening of fatty acid synthase inhibitors against thioesterase domain
title_fullStr Computational screening of fatty acid synthase inhibitors against thioesterase domain
title_full_unstemmed Computational screening of fatty acid synthase inhibitors against thioesterase domain
title_sort computational screening of fatty acid synthase inhibitors against thioesterase domain
publishDate 2018
url https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85038030583&origin=inward
http://cmuir.cmu.ac.th/jspui/handle/6653943832/43422
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