Exploration of structural and physicochemical requirements and search of virtual hits for aminopeptidase N inhibitors
Identifieur interne : 000587 ( Istex/Corpus ); précédent : 000586; suivant : 000588Exploration of structural and physicochemical requirements and search of virtual hits for aminopeptidase N inhibitors
Auteurs : Amit K. Halder ; Achintya Saha ; Tarun JhaSource :
- Molecular Diversity [ 1381-1991 ] ; 2013-02-01.
English descriptors
- KwdEn :
Abstract
Abstract: Aminopeptidase N (APN) inhibitors have been reported to be effective in treating of life threatening diseases including cancer. Validated ligand- and structure-based pharmacophore mapping approaches were combined with Bayesian modeling and recursive partitioning to identify structural and physicochemical requirements for highly active APN inhibitors. Based on the assumption that ligand- and structure-based pharmacophore models are complementary, the efficacy of ‘multiple pharmacophore screening’ for filtering true positive virtual hits was investigated. These multiple pharmacophore screening methods were utilized to search novel virtual hits for APN inhibition. The number of hits was refined and reduced by recursive partitioning, drug-likeliness, pharmacokinetic property prediction, and comparative molecular-docking studies. Four compounds were proposed as the potential virtual hits for APN enzyme inhibition.
Url:
DOI: 10.1007/s11030-013-9422-5
Links to Exploration step
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<front><div type="abstract" xml:lang="en">Abstract: Aminopeptidase N (APN) inhibitors have been reported to be effective in treating of life threatening diseases including cancer. Validated ligand- and structure-based pharmacophore mapping approaches were combined with Bayesian modeling and recursive partitioning to identify structural and physicochemical requirements for highly active APN inhibitors. Based on the assumption that ligand- and structure-based pharmacophore models are complementary, the efficacy of ‘multiple pharmacophore screening’ for filtering true positive virtual hits was investigated. These multiple pharmacophore screening methods were utilized to search novel virtual hits for APN inhibition. The number of hits was refined and reduced by recursive partitioning, drug-likeliness, pharmacokinetic property prediction, and comparative molecular-docking studies. Four compounds were proposed as the potential virtual hits for APN enzyme inhibition.</div>
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<item><term>APN</term>
<term>Aminopeptidase N</term>
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<item><term>A</term>
<term>Hydrogen-bond acceptor</term>
</item>
<item><term>BD</term>
<term>Binding database</term>
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<item><term>D</term>
<term>Hydrogen-bond donor</term>
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<item><term>MFASA</term>
<term>Molecular fractional polar surface area</term>
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<item><term>MPSA</term>
<term>Molecular polar surface area</term>
</item>
<item><term>MW</term>
<term>Molecular weight</term>
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<item><term>$$n$$ HBA</term>
<term>Number of hydrogen-bond acceptor</term>
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<term>Number of hydrogen-bond donor</term>
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<term>Number of fragments</term>
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<item><term>$$n$$ RB</term>
<term>Number of rotatable bonds</term>
</item>
<item><term>$$n$$ PA</term>
<term>Number of positive atoms</term>
</item>
<item><term>$$n$$ R</term>
<term>Number of rings</term>
</item>
<item><term>$$n$$ ArR</term>
<term>Number of aromatic rings</term>
</item>
<item><term>P</term>
<term>Positive ionisable</term>
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<item><term>R</term>
<term>Ring aromatic</term>
</item>
<item><term>RP</term>
<term>Recursive partition</term>
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<OnlineDate><Year>2013</Year>
<Month>1</Month>
<Day>23</Day>
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<CopyrightYear>2013</CopyrightYear>
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<ArticleHeader><AuthorGroup><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Amit</GivenName>
<GivenName>K.</GivenName>
<FamilyName>Halder</FamilyName>
</AuthorName>
</Author>
<Author AffiliationIDS="Aff2"><AuthorName DisplayOrder="Western"><GivenName>Achintya</GivenName>
<FamilyName>Saha</FamilyName>
</AuthorName>
</Author>
<Author AffiliationIDS="Aff1" CorrespondingAffiliationID="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Tarun</GivenName>
<FamilyName>Jha</FamilyName>
</AuthorName>
<Contact><Phone>+919433187443</Phone>
<Fax>+913324146927</Fax>
<Email>tjupharm@yahoo.com</Email>
</Contact>
</Author>
<Affiliation ID="Aff1"><OrgDivision>Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology</OrgDivision>
<OrgName>Jadavpur University</OrgName>
<OrgAddress><Postbox>P.O. Box 17020</Postbox>
<City>Kolkata</City>
<Postcode>700032</Postcode>
<Country Code="IN">India</Country>
</OrgAddress>
</Affiliation>
<Affiliation ID="Aff2"><OrgDivision>Department of Chemical Technology</OrgDivision>
<OrgName>University of Calcutta</OrgName>
<OrgAddress><Street>92, APC Ray Road</Street>
<City>Kolkata</City>
<Postcode>700009</Postcode>
<Country Code="IN">India</Country>
</OrgAddress>
</Affiliation>
</AuthorGroup>
<Abstract ID="Abs1" Language="En" OutputMedium="All"><Heading>Abstract</Heading>
<Para>Aminopeptidase N (APN) inhibitors have been reported to be effective in treating of life threatening diseases including cancer. Validated ligand- and structure-based pharmacophore mapping approaches were combined with Bayesian modeling and recursive partitioning to identify structural and physicochemical requirements for highly active APN inhibitors. Based on the assumption that ligand- and structure-based pharmacophore models are complementary, the efficacy of ‘multiple pharmacophore screening’ for filtering true positive virtual hits was investigated. These multiple pharmacophore screening methods were utilized to search novel virtual hits for APN inhibition. The number of hits was refined and reduced by recursive partitioning, drug-likeliness, pharmacokinetic property prediction, and comparative molecular-docking studies. Four compounds were proposed as the potential virtual hits for APN enzyme inhibition.</Para>
</Abstract>
<KeywordGroup Language="En" OutputMedium="All"><Heading>Keywords</Heading>
<Keyword>Aminopeptidase N</Keyword>
<Keyword>Pharmacophore mapping</Keyword>
<Keyword>Bayesian modeling</Keyword>
<Keyword>Recursive partitioning</Keyword>
<Keyword>Molecular docking</Keyword>
<Keyword>Virtual hits</Keyword>
</KeywordGroup>
<AbbreviationGroup><Heading>Abbreviations</Heading>
<DefinitionList><DefinitionListEntry><Term>APN</Term>
<Description><Para>Aminopeptidase N</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>A</Term>
<Description><Para>Hydrogen-bond acceptor</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>BD</Term>
<Description><Para>Binding database</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>D</Term>
<Description><Para>Hydrogen-bond donor</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>MFASA</Term>
<Description><Para>Molecular fractional polar surface area</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>MPSA</Term>
<Description><Para>Molecular polar surface area</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>MW</Term>
<Description><Para>Molecular weight</Para>
</Description>
</DefinitionListEntry>
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</InlineMediaObject>
<EquationSource Format="TEX">$$n$$</EquationSource>
</InlineEquation>
HBA</Term>
<Description><Para>Number of hydrogen-bond acceptor</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term><InlineEquation ID="IEq2"><InlineMediaObject><ImageObject Color="BlackWhite" FileRef="11030_2013_9422_Article_IEq2.gif" Format="GIF" Rendition="HTML" Type="Linedraw"></ImageObject>
</InlineMediaObject>
<EquationSource Format="TEX">$$n$$</EquationSource>
</InlineEquation>
HBD</Term>
<Description><Para>Number of hydrogen-bond donor</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term><InlineEquation ID="IEq3"><InlineMediaObject><ImageObject Color="BlackWhite" FileRef="11030_2013_9422_Article_IEq3.gif" Format="GIF" Rendition="HTML" Type="Linedraw"></ImageObject>
</InlineMediaObject>
<EquationSource Format="TEX">$$n$$</EquationSource>
</InlineEquation>
Fr</Term>
<Description><Para>Number of fragments</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term><InlineEquation ID="IEq4"><InlineMediaObject><ImageObject Color="BlackWhite" FileRef="11030_2013_9422_Article_IEq4.gif" Format="GIF" Rendition="HTML" Type="Linedraw"></ImageObject>
</InlineMediaObject>
<EquationSource Format="TEX">$$n$$</EquationSource>
</InlineEquation>
RB</Term>
<Description><Para>Number of rotatable bonds</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term><InlineEquation ID="IEq5"><InlineMediaObject><ImageObject Color="BlackWhite" FileRef="11030_2013_9422_Article_IEq5.gif" Format="GIF" Rendition="HTML" Type="Linedraw"></ImageObject>
</InlineMediaObject>
<EquationSource Format="TEX">$$n$$</EquationSource>
</InlineEquation>
PA</Term>
<Description><Para>Number of positive atoms</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term><InlineEquation ID="IEq6"><InlineMediaObject><ImageObject Color="BlackWhite" FileRef="11030_2013_9422_Article_IEq6.gif" Format="GIF" Rendition="HTML" Type="Linedraw"></ImageObject>
</InlineMediaObject>
<EquationSource Format="TEX">$$n$$</EquationSource>
</InlineEquation>
R</Term>
<Description><Para>Number of rings</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term><InlineEquation ID="IEq7"><InlineMediaObject><ImageObject Color="BlackWhite" FileRef="11030_2013_9422_Article_IEq7.gif" Format="GIF" Rendition="HTML" Type="Linedraw"></ImageObject>
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<EquationSource Format="TEX">$$n$$</EquationSource>
</InlineEquation>
ArR</Term>
<Description><Para>Number of aromatic rings</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>P</Term>
<Description><Para>Positive ionisable</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>R</Term>
<Description><Para>Ring aromatic</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>RP</Term>
<Description><Para>Recursive partition</Para>
</Description>
</DefinitionListEntry>
<DefinitionListEntry><Term>Y</Term>
<Description><Para>Hydrophobic</Para>
</Description>
</DefinitionListEntry>
</DefinitionList>
</AbbreviationGroup>
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<abstract lang="en">Abstract: Aminopeptidase N (APN) inhibitors have been reported to be effective in treating of life threatening diseases including cancer. Validated ligand- and structure-based pharmacophore mapping approaches were combined with Bayesian modeling and recursive partitioning to identify structural and physicochemical requirements for highly active APN inhibitors. Based on the assumption that ligand- and structure-based pharmacophore models are complementary, the efficacy of ‘multiple pharmacophore screening’ for filtering true positive virtual hits was investigated. These multiple pharmacophore screening methods were utilized to search novel virtual hits for APN inhibition. The number of hits was refined and reduced by recursive partitioning, drug-likeliness, pharmacokinetic property prediction, and comparative molecular-docking studies. Four compounds were proposed as the potential virtual hits for APN enzyme inhibition.</abstract>
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<subject lang="en"><genre>Keywords</genre>
<topic>Aminopeptidase N</topic>
<topic>Pharmacophore mapping</topic>
<topic>Bayesian modeling</topic>
<topic>Recursive partitioning</topic>
<topic>Molecular docking</topic>
<topic>Virtual hits</topic>
</subject>
<subject><genre>Abbreviations</genre>
<topic>APN : Aminopeptidase N</topic>
<topic>A : Hydrogen-bond acceptor</topic>
<topic>BD : Binding database</topic>
<topic>D : Hydrogen-bond donor</topic>
<topic>MFASA : Molecular fractional polar surface area</topic>
<topic>MPSA : Molecular polar surface area</topic>
<topic>MW : Molecular weight</topic>
<topic>$$n$$ HBA : Number of hydrogen-bond acceptor</topic>
<topic>$$n$$ HBD : Number of hydrogen-bond donor</topic>
<topic>$$n$$ Fr : Number of fragments</topic>
<topic>$$n$$ RB : Number of rotatable bonds</topic>
<topic>$$n$$ PA : Number of positive atoms</topic>
<topic>$$n$$ R : Number of rings</topic>
<topic>$$n$$ ArR : Number of aromatic rings</topic>
<topic>P : Positive ionisable</topic>
<topic>R : Ring aromatic</topic>
<topic>RP : Recursive partition</topic>
<topic>Y : Hydrophobic</topic>
</subject>
<relatedItem type="host"><titleInfo><title>Molecular Diversity</title>
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<originInfo><publisher>Springer</publisher>
<dateIssued encoding="w3cdtf">2013-02-05</dateIssued>
<copyrightDate encoding="w3cdtf">2013</copyrightDate>
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<topic authority="SpringerSubjectCodes" authorityURI="SCC22008">Polymer Sciences</topic>
<topic authority="SpringerSubjectCodes" authorityURI="SCF00008">Pharmacy</topic>
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<identifier type="ISSN">1381-1991</identifier>
<identifier type="eISSN">1573-501X</identifier>
<identifier type="JournalID">11030</identifier>
<identifier type="IssueArticleCount">15</identifier>
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