A 3D QSAR Model of 17β‐HSD1 Inhibitors Based on a Thieno[2,3‐d]pyrimidin‐4(3H)‐one Core Applying Molecular Dynamics Simulations and Ligand–Protein Docking
Identifieur interne : 000720 ( Main/Exploration ); précédent : 000719; suivant : 000721A 3D QSAR Model of 17β‐HSD1 Inhibitors Based on a Thieno[2,3‐d]pyrimidin‐4(3H)‐one Core Applying Molecular Dynamics Simulations and Ligand–Protein Docking
Auteurs : Sampo Karkola [Finlande] ; Annamaria Lilienkampf [Finlande] ; Kristiina W H L [Finlande]Source :
- ChemMedChem [ 1860-7179 ] ; 2008-03-14.
English descriptors
- KwdEn :
Abstract
The 17β‐hydroxysteroid dehydrogenase type 1 (17β‐HSD1) enzyme plays a crucial role in female hormonal regulation by catalysing the NADPH‐dependent reduction of the less potent estrone E1 into the biologically active estradiol E2. Because 17β‐HSD1 is a key enzyme in E2 biosynthesis, it has emerged as an attractive drug target for inhibitor development. Herein we report the plausible binding modes and a 3D QSAR model of 17β‐HSD1 inhibitors based on a (di)cycloalkenothieno[2,3‐d]pyrimidin‐4(3H)‐one core. Two generated enzyme complexes with potent inhibitors were subjected to molecular dynamics simulation to mimic the dynamic process of inhibitor binding. A set of 17β‐HSD1 inhibitors based on the thieno[2,3‐d]pyrimidin‐4(3H)‐one core were docked into the resulting active site, and a CoMFA model employing the most extensive training set to date was generated. The model was validated with an external test set. Active site residues involved in inhibitor binding and CoMFA fields for steric and electrostatic interactions were identified. The model will be used to guide structural modifications of 17β‐HSD1 inhibitors based on a thieno[2,3‐d]pyrimidin‐4(3H)‐one core in order to improve the biological activity as well as in the design of novel 17β‐HSD1 inhibitors.
Url:
DOI: 10.1002/cmdc.200700271
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream Istex, to step Corpus: 001A28
- to stream Istex, to step Curation: 001A28
- to stream Istex, to step Checkpoint: 000413
- to stream Main, to step Merge: 000731
- to stream Main, to step Curation: 000720
Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">A 3D QSAR Model of 17β‐HSD1 Inhibitors Based on a Thieno[2,3‐d]pyrimidin‐4(3H)‐one Core Applying Molecular Dynamics Simulations and Ligand–Protein Docking</title><author><name sortKey="Karkola, Sampo" sort="Karkola, Sampo" uniqKey="Karkola S" first="Sampo" last="Karkola">Sampo Karkola</name></author><author><name sortKey="Lilienkampf, Annamaria" sort="Lilienkampf, Annamaria" uniqKey="Lilienkampf A" first="Annamaria" last="Lilienkampf">Annamaria Lilienkampf</name></author><author><name sortKey="W H L, Kristiina" sort="W H L, Kristiina" uniqKey="W H L K" first="Kristiina" last="W H L">Kristiina W H L</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:0D09BE70A4D8BB9C96958FF9B8179F93D5D54ADC</idno><date when="2008" year="2008">2008</date><idno type="doi">10.1002/cmdc.200700271</idno><idno type="url">https://api.istex.fr/document/0D09BE70A4D8BB9C96958FF9B8179F93D5D54ADC/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001A28</idno><idno type="wicri:Area/Istex/Curation">001A28</idno><idno type="wicri:Area/Istex/Checkpoint">000413</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Checkpoint">000413</idno><idno type="wicri:doubleKey">1860-7179:2008:Karkola S:a:d:qsar</idno><idno type="wicri:Area/Main/Merge">000731</idno><idno type="wicri:Area/Main/Curation">000720</idno><idno type="wicri:Area/Main/Exploration">000720</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">A 3D QSAR Model of 17β‐HSD1 Inhibitors Based on a Thieno[2,3‐d]pyrimidin‐4(3H)‐one Core Applying Molecular Dynamics Simulations and Ligand–Protein Docking</title><author><name sortKey="Karkola, Sampo" sort="Karkola, Sampo" uniqKey="Karkola S" first="Sampo" last="Karkola">Sampo Karkola</name><affiliation wicri:level="4"><orgName type="university">Université d'Helsinki</orgName><country>Finlande</country><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName></affiliation></author><author><name sortKey="Lilienkampf, Annamaria" sort="Lilienkampf, Annamaria" uniqKey="Lilienkampf A" first="Annamaria" last="Lilienkampf">Annamaria Lilienkampf</name><affiliation wicri:level="4"><orgName type="university">Université d'Helsinki</orgName><country>Finlande</country><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName></affiliation></author><author><name sortKey="W H L, Kristiina" sort="W H L, Kristiina" uniqKey="W H L K" first="Kristiina" last="W H L">Kristiina W H L</name><affiliation wicri:level="1"><country wicri:rule="url">Finlande</country></affiliation><affiliation wicri:level="4"><orgName type="university">Université d'Helsinki</orgName><country>Finlande</country><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">ChemMedChem</title><title level="j" type="sub">Chemistry Enabling Drug Discovery</title><title level="j" type="abbrev">ChemMedChem</title><idno type="ISSN">1860-7179</idno><idno type="eISSN">1860-7187</idno><imprint><publisher>WILEY‐VCH Verlag</publisher><pubPlace>Weinheim</pubPlace><date type="published" when="2008-03-14">2008-03-14</date><biblScope unit="volume">3</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="461">461</biblScope><biblScope unit="page" to="472">472</biblScope></imprint><idno type="ISSN">1860-7179</idno></series><idno type="istex">0D09BE70A4D8BB9C96958FF9B8179F93D5D54ADC</idno><idno type="DOI">10.1002/cmdc.200700271</idno><idno type="ArticleID">CMDC200700271</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1860-7179</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>17β‐HSD1</term><term>3D QSAR</term><term>breast cancer</term><term>drug design</term><term>molecular modeling</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The 17β‐hydroxysteroid dehydrogenase type 1 (17β‐HSD1) enzyme plays a crucial role in female hormonal regulation by catalysing the NADPH‐dependent reduction of the less potent estrone E1 into the biologically active estradiol E2. Because 17β‐HSD1 is a key enzyme in E2 biosynthesis, it has emerged as an attractive drug target for inhibitor development. Herein we report the plausible binding modes and a 3D QSAR model of 17β‐HSD1 inhibitors based on a (di)cycloalkenothieno[2,3‐d]pyrimidin‐4(3H)‐one core. Two generated enzyme complexes with potent inhibitors were subjected to molecular dynamics simulation to mimic the dynamic process of inhibitor binding. A set of 17β‐HSD1 inhibitors based on the thieno[2,3‐d]pyrimidin‐4(3H)‐one core were docked into the resulting active site, and a CoMFA model employing the most extensive training set to date was generated. The model was validated with an external test set. Active site residues involved in inhibitor binding and CoMFA fields for steric and electrostatic interactions were identified. The model will be used to guide structural modifications of 17β‐HSD1 inhibitors based on a thieno[2,3‐d]pyrimidin‐4(3H)‐one core in order to improve the biological activity as well as in the design of novel 17β‐HSD1 inhibitors.</div></front></TEI><affiliations><list><country><li>Finlande</li></country><region><li>Uusimaa</li></region><settlement><li>Helsinki</li></settlement><orgName><li>Université d'Helsinki</li></orgName></list><tree><country name="Finlande"><region name="Uusimaa"><name sortKey="Karkola, Sampo" sort="Karkola, Sampo" uniqKey="Karkola S" first="Sampo" last="Karkola">Sampo Karkola</name></region><name sortKey="Lilienkampf, Annamaria" sort="Lilienkampf, Annamaria" uniqKey="Lilienkampf A" first="Annamaria" last="Lilienkampf">Annamaria Lilienkampf</name><name sortKey="W H L, Kristiina" sort="W H L, Kristiina" uniqKey="W H L K" first="Kristiina" last="W H L">Kristiina W H L</name><name sortKey="W H L, Kristiina" sort="W H L, Kristiina" uniqKey="W H L K" first="Kristiina" last="W H L">Kristiina W H L</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Eau/explor/LotaV3/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000720 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000720 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Eau
|area= LotaV3
|flux= Main
|étape= Exploration
|type= RBID
|clé= ISTEX:0D09BE70A4D8BB9C96958FF9B8179F93D5D54ADC
|texte= A 3D QSAR Model of 17β‐HSD1 Inhibitors Based on a Thieno[2,3‐d]pyrimidin‐4(3H)‐one Core Applying Molecular Dynamics Simulations and Ligand–Protein Docking
}}
| This area was generated with Dilib version V0.6.39. |  |