3D QSAR (COMFA) of a series of potent and highly selective VLA-4 antagonists View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2002-03

AUTHORS

Juswinder Singh, Herman van Vlijmen, Wen-Cherng Lee, Yusheng Liao, Ko-Chung Lin, Humayun Ateeq, Julio Cuervo, Craig Zimmerman, Charles Hammond, Michael Karpusas, Rex Palmer, Tapan Chattopadhyay, Steven P. Adams

ABSTRACT

The integrin VLA-4 (alpha4,beta1) is involved in the migration of white blood cells to sites of inflammation, and is implicated in the pathology of a variety of diseases including asthma and multiple sclerosis. We report the structure-activity relationships of a series of VLA-4 antagonists that were based upon the integrin-binding sequence of the connecting segment peptide of fibronectin (Leu-Asp-Val), and of VCAM-1 (Ile-Asp-Ser), both natural ligands of VLA-4. We explore variation in the ligand derived peptide portion of these antagonists and also in the novel N-terminal cap, which have discovered through chemical optimization, and which confers high affinity and selectivity. Using the X-ray derived conformation of the Ile-Asp-Ser region of VCAM-1, we rationalize the structure-activity relationships of these antagonists using 3D QSAR (COMFA). The COMFA model was found to be highly predictive with a cross-validated R2CV of 0.7 and a PRESS of 0.49. The robustness of the model was confirmed by testing the influence of various parameters, including grid size, column filtering, as well as the role of orientation of the aligned molecules. Our results suggest that the VCAM-1 structure is useful in generating highly predictive models of our VLA-4 antagonists. The COMFA model coupled with the knowledge that the peptide amides are tolerant to methylation should prove useful in future peptidomimetic design studies. More... »

PAGES

201-211

Identifiers

URI

http://scigraph.springernature.com/pub.10.1023/a:1020130418084

DOI

http://dx.doi.org/10.1023/a:1020130418084

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1030174250

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/12363218


Indexing Status Check whether this publication has been indexed by Scopus and Web Of Science using the SN Indexing Status Tool
Incoming Citations Browse incoming citations for this publication using opencitations.net

JSON-LD is the canonical representation for SciGraph data.

TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

[
  {
    "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
    "about": [
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/1107", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Immunology", 
        "type": "DefinedTerm"
      }, 
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/11", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Medical and Health Sciences", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Binding Sites", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Computer-Aided Design", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Crystallography, X-Ray", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Drug Design", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Humans", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "In Vitro Techniques", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Integrin alpha4beta1", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Ligands", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Methylation", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Models, Molecular", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Molecular Conformation", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Oligopeptides", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Quantitative Structure-Activity Relationship", 
        "type": "DefinedTerm"
      }
    ], 
    "author": [
      {
        "affiliation": {
          "alternateName": "Biogen (United States)", 
          "id": "https://www.grid.ac/institutes/grid.417832.b", 
          "name": [
            "Biogen Inc, 12 Cambridge Center, MA02142, Cambridge, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Singh", 
        "givenName": "Juswinder", 
        "id": "sg:person.01020306447.41", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01020306447.41"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Biogen (United States)", 
          "id": "https://www.grid.ac/institutes/grid.417832.b", 
          "name": [
            "Biogen Inc, 12 Cambridge Center, MA02142, Cambridge, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Vlijmen", 
        "givenName": "Herman van", 
        "id": "sg:person.01135422566.97", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01135422566.97"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Biogen (United States)", 
          "id": "https://www.grid.ac/institutes/grid.417832.b", 
          "name": [
            "Biogen Inc, 12 Cambridge Center, MA02142, Cambridge, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Lee", 
        "givenName": "Wen-Cherng", 
        "id": "sg:person.01157537767.39", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01157537767.39"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Biogen (United States)", 
          "id": "https://www.grid.ac/institutes/grid.417832.b", 
          "name": [
            "Biogen Inc, 12 Cambridge Center, MA02142, Cambridge, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Liao", 
        "givenName": "Yusheng", 
        "id": "sg:person.01270362723.85", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01270362723.85"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Biogen (United States)", 
          "id": "https://www.grid.ac/institutes/grid.417832.b", 
          "name": [
            "Biogen Inc, 12 Cambridge Center, MA02142, Cambridge, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Lin", 
        "givenName": "Ko-Chung", 
        "id": "sg:person.01244761400.24", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01244761400.24"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Biogen (United States)", 
          "id": "https://www.grid.ac/institutes/grid.417832.b", 
          "name": [
            "Biogen Inc, 12 Cambridge Center, MA02142, Cambridge, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Ateeq", 
        "givenName": "Humayun", 
        "id": "sg:person.01313074600.49", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01313074600.49"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Biogen (United States)", 
          "id": "https://www.grid.ac/institutes/grid.417832.b", 
          "name": [
            "Biogen Inc, 12 Cambridge Center, MA02142, Cambridge, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Cuervo", 
        "givenName": "Julio", 
        "id": "sg:person.01155551412.12", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01155551412.12"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Biogen (United States)", 
          "id": "https://www.grid.ac/institutes/grid.417832.b", 
          "name": [
            "Biogen Inc, 12 Cambridge Center, MA02142, Cambridge, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Zimmerman", 
        "givenName": "Craig", 
        "id": "sg:person.0703717100.51", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0703717100.51"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Biogen (United States)", 
          "id": "https://www.grid.ac/institutes/grid.417832.b", 
          "name": [
            "Biogen Inc, 12 Cambridge Center, MA02142, Cambridge, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Hammond", 
        "givenName": "Charles", 
        "id": "sg:person.01066260700.27", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01066260700.27"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Biogen (United States)", 
          "id": "https://www.grid.ac/institutes/grid.417832.b", 
          "name": [
            "Biogen Inc, 12 Cambridge Center, MA02142, Cambridge, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Karpusas", 
        "givenName": "Michael", 
        "id": "sg:person.010077157364.71", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.010077157364.71"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University College London", 
          "id": "https://www.grid.ac/institutes/grid.83440.3b", 
          "name": [
            "Dept. of Crystallography, Birkbeck College, University of London, Malet Street, WC1E 7HX, London, U.K"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Palmer", 
        "givenName": "Rex", 
        "id": "sg:person.01013714776.39", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01013714776.39"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "University College London", 
          "id": "https://www.grid.ac/institutes/grid.83440.3b", 
          "name": [
            "Dept. of Crystallography, Birkbeck College, University of London, Malet Street, WC1E 7HX, London, U.K"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Chattopadhyay", 
        "givenName": "Tapan", 
        "id": "sg:person.01222236272.86", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01222236272.86"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Biogen (United States)", 
          "id": "https://www.grid.ac/institutes/grid.417832.b", 
          "name": [
            "Biogen Inc, 12 Cambridge Center, MA02142, Cambridge, USA"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Adams", 
        "givenName": "Steven P.", 
        "id": "sg:person.01361471370.91", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01361471370.91"
        ], 
        "type": "Person"
      }
    ], 
    "citation": [
      {
        "id": "https://doi.org/10.1172/jci117032", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1003779133"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1073/pnas.92.12.5714", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1005946835"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1172/jci117962", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1009515471"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1073/pnas.90.22.10494", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1013279571"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1172/jci119571", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1014773540"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.3109/15419069509081293", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1036241044"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1159/000237468", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1038691915"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1002/9780470514719.ch13", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1043823658"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1172/jci116575", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1046310997"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1083/jcb.125.6.1395", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1051217174"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/373539a0", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1051713115", 
          "https://doi.org/10.1038/373539a0"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1021/bi980311a", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1055215592"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1021/bi980311a", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1055215592"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1021/ja00226a005", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1055715782"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1021/jm00007a003", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1055932355"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1021/jm00077a003", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1055934333"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1021/jm980673g", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1055959172"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1021/jm980673g", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1055959172"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.2337/diab.43.4.529", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1070737298"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1077688636", 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1082391460", 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1082425280", 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.3233/hab-1997-8102", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1083133275"
        ], 
        "type": "CreativeWork"
      }
    ], 
    "datePublished": "2002-03", 
    "datePublishedReg": "2002-03-01", 
    "description": "The integrin VLA-4 (alpha4,beta1) is involved in the migration of white blood cells to sites of inflammation, and is implicated in the pathology of a variety of diseases including asthma and multiple sclerosis. We report the structure-activity relationships of a series of VLA-4 antagonists that were based upon the integrin-binding sequence of the connecting segment peptide of fibronectin (Leu-Asp-Val), and of VCAM-1 (Ile-Asp-Ser), both natural ligands of VLA-4. We explore variation in the ligand derived peptide portion of these antagonists and also in the novel N-terminal cap, which have discovered through chemical optimization, and which confers high affinity and selectivity. Using the X-ray derived conformation of the Ile-Asp-Ser region of VCAM-1, we rationalize the structure-activity relationships of these antagonists using 3D QSAR (COMFA). The COMFA model was found to be highly predictive with a cross-validated R2CV of 0.7 and a PRESS of 0.49. The robustness of the model was confirmed by testing the influence of various parameters, including grid size, column filtering, as well as the role of orientation of the aligned molecules. Our results suggest that the VCAM-1 structure is useful in generating highly predictive models of our VLA-4 antagonists. The COMFA model coupled with the knowledge that the peptide amides are tolerant to methylation should prove useful in future peptidomimetic design studies.", 
    "genre": "research_article", 
    "id": "sg:pub.10.1023/a:1020130418084", 
    "inLanguage": [
      "en"
    ], 
    "isAccessibleForFree": false, 
    "isPartOf": [
      {
        "id": "sg:journal.1105375", 
        "issn": [
          "0928-2866", 
          "1573-9023"
        ], 
        "name": "Journal of Computer-Aided Molecular Design", 
        "type": "Periodical"
      }, 
      {
        "issueNumber": "3", 
        "type": "PublicationIssue"
      }, 
      {
        "type": "PublicationVolume", 
        "volumeNumber": "16"
      }
    ], 
    "name": "3D QSAR (COMFA) of a series of potent and highly selective VLA-4 antagonists", 
    "pagination": "201-211", 
    "productId": [
      {
        "name": "readcube_id", 
        "type": "PropertyValue", 
        "value": [
          "8fbf133ed460174043cd46dbdb61396b7188ea7caa1f91cce40475badad6349e"
        ]
      }, 
      {
        "name": "pubmed_id", 
        "type": "PropertyValue", 
        "value": [
          "12363218"
        ]
      }, 
      {
        "name": "nlm_unique_id", 
        "type": "PropertyValue", 
        "value": [
          "8710425"
        ]
      }, 
      {
        "name": "doi", 
        "type": "PropertyValue", 
        "value": [
          "10.1023/a:1020130418084"
        ]
      }, 
      {
        "name": "dimensions_id", 
        "type": "PropertyValue", 
        "value": [
          "pub.1030174250"
        ]
      }
    ], 
    "sameAs": [
      "https://doi.org/10.1023/a:1020130418084", 
      "https://app.dimensions.ai/details/publication/pub.1030174250"
    ], 
    "sdDataset": "articles", 
    "sdDatePublished": "2019-04-10T20:45", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
      "type": "Organization"
    }, 
    "sdSource": "s3://com-uberresearch-data-dimensions-target-20181106-alternative/cleanup/v134/2549eaecd7973599484d7c17b260dba0a4ecb94b/merge/v9/a6c9fde33151104705d4d7ff012ea9563521a3ce/jats-lookup/v90/0000000001_0000000264/records_8684_00000506.jsonl", 
    "type": "ScholarlyArticle", 
    "url": "http://link.springer.com/10.1023%2FA%3A1020130418084"
  }
]
 

Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1023/a:1020130418084'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1023/a:1020130418084'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1023/a:1020130418084'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1023/a:1020130418084'


 

This table displays all metadata directly associated to this object as RDF triples.

269 TRIPLES      21 PREDICATES      63 URIs      34 LITERALS      22 BLANK NODES

Subject Predicate Object
1 sg:pub.10.1023/a:1020130418084 schema:about N09f136c6d5ba4c0199d258360848d69d
2 N22bb99aa4be742b6bff2f8465d103b44
3 N3f43584a0c024d24a1fe13005f0c346e
4 N6bdb467289794c218e74cb0a246f347d
5 N6dea6aabba4d43c98783c84c08d321ce
6 N74fffaf6c97d4d289a8cbc7cd2a11bee
7 N78bfe0c324b441c28fd21284c872e395
8 N791acb153efa400eb16b22502a84bbb0
9 N7f6ae8887b534840949769d7125554a6
10 N8dc002cb8319444db41d860f469f34f3
11 Nb59646a86f3c487186da2c64a5b4bf62
12 Ne06f9f18aa314b83aa7bc1f0b03af4d5
13 Ned7ea3944b4b44f7bfd10be7041c059f
14 anzsrc-for:11
15 anzsrc-for:1107
16 schema:author N529797836d834ca6b4fdf94441ebfa83
17 schema:citation sg:pub.10.1038/373539a0
18 https://app.dimensions.ai/details/publication/pub.1077688636
19 https://app.dimensions.ai/details/publication/pub.1082391460
20 https://app.dimensions.ai/details/publication/pub.1082425280
21 https://doi.org/10.1002/9780470514719.ch13
22 https://doi.org/10.1021/bi980311a
23 https://doi.org/10.1021/ja00226a005
24 https://doi.org/10.1021/jm00007a003
25 https://doi.org/10.1021/jm00077a003
26 https://doi.org/10.1021/jm980673g
27 https://doi.org/10.1073/pnas.90.22.10494
28 https://doi.org/10.1073/pnas.92.12.5714
29 https://doi.org/10.1083/jcb.125.6.1395
30 https://doi.org/10.1159/000237468
31 https://doi.org/10.1172/jci116575
32 https://doi.org/10.1172/jci117032
33 https://doi.org/10.1172/jci117962
34 https://doi.org/10.1172/jci119571
35 https://doi.org/10.2337/diab.43.4.529
36 https://doi.org/10.3109/15419069509081293
37 https://doi.org/10.3233/hab-1997-8102
38 schema:datePublished 2002-03
39 schema:datePublishedReg 2002-03-01
40 schema:description The integrin VLA-4 (alpha4,beta1) is involved in the migration of white blood cells to sites of inflammation, and is implicated in the pathology of a variety of diseases including asthma and multiple sclerosis. We report the structure-activity relationships of a series of VLA-4 antagonists that were based upon the integrin-binding sequence of the connecting segment peptide of fibronectin (Leu-Asp-Val), and of VCAM-1 (Ile-Asp-Ser), both natural ligands of VLA-4. We explore variation in the ligand derived peptide portion of these antagonists and also in the novel N-terminal cap, which have discovered through chemical optimization, and which confers high affinity and selectivity. Using the X-ray derived conformation of the Ile-Asp-Ser region of VCAM-1, we rationalize the structure-activity relationships of these antagonists using 3D QSAR (COMFA). The COMFA model was found to be highly predictive with a cross-validated R2CV of 0.7 and a PRESS of 0.49. The robustness of the model was confirmed by testing the influence of various parameters, including grid size, column filtering, as well as the role of orientation of the aligned molecules. Our results suggest that the VCAM-1 structure is useful in generating highly predictive models of our VLA-4 antagonists. The COMFA model coupled with the knowledge that the peptide amides are tolerant to methylation should prove useful in future peptidomimetic design studies.
41 schema:genre research_article
42 schema:inLanguage en
43 schema:isAccessibleForFree false
44 schema:isPartOf N4724f071632e4c7bb62751f651bbd93f
45 N677a7cc04b8a43abb6db98825aca62dd
46 sg:journal.1105375
47 schema:name 3D QSAR (COMFA) of a series of potent and highly selective VLA-4 antagonists
48 schema:pagination 201-211
49 schema:productId N1b1d9586e4de45a99f90ba8e8ab6c3f1
50 Na151de3fdc6f401fa597abd01ca0ee7e
51 Nb66c42a1472c4e83b47fd109c7d8facf
52 Nbb0aed8cfe8e443ba16be392d36a6174
53 Nf3ff0b6a9aa74c7d806fea087ec02ee9
54 schema:sameAs https://app.dimensions.ai/details/publication/pub.1030174250
55 https://doi.org/10.1023/a:1020130418084
56 schema:sdDatePublished 2019-04-10T20:45
57 schema:sdLicense https://scigraph.springernature.com/explorer/license/
58 schema:sdPublisher N6de31aad88834ed1b63c7a47727f8f18
59 schema:url http://link.springer.com/10.1023%2FA%3A1020130418084
60 sgo:license sg:explorer/license/
61 sgo:sdDataset articles
62 rdf:type schema:ScholarlyArticle
63 N09f136c6d5ba4c0199d258360848d69d schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
64 schema:name Models, Molecular
65 rdf:type schema:DefinedTerm
66 N0f2a0749ba6e40a7b6c8f252846b170a rdf:first sg:person.01157537767.39
67 rdf:rest Nda8ed59b8db44a2e9b09ce3c76e94856
68 N1b1d9586e4de45a99f90ba8e8ab6c3f1 schema:name dimensions_id
69 schema:value pub.1030174250
70 rdf:type schema:PropertyValue
71 N20aac324c022492fae1b89862c94f22f rdf:first sg:person.01244761400.24
72 rdf:rest N6101358dd1fd405ea67aca9e4fff655d
73 N22bb99aa4be742b6bff2f8465d103b44 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
74 schema:name Crystallography, X-Ray
75 rdf:type schema:DefinedTerm
76 N2675522f3215479398e1fb2c31bb7501 rdf:first sg:person.01155551412.12
77 rdf:rest N72bd283fe1d44583927190605034f3b7
78 N3f43584a0c024d24a1fe13005f0c346e schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
79 schema:name Humans
80 rdf:type schema:DefinedTerm
81 N4724f071632e4c7bb62751f651bbd93f schema:volumeNumber 16
82 rdf:type schema:PublicationVolume
83 N529797836d834ca6b4fdf94441ebfa83 rdf:first sg:person.01020306447.41
84 rdf:rest N6d81f1708fab4d9ea6ff02d10a362b73
85 N6101358dd1fd405ea67aca9e4fff655d rdf:first sg:person.01313074600.49
86 rdf:rest N2675522f3215479398e1fb2c31bb7501
87 N677a7cc04b8a43abb6db98825aca62dd schema:issueNumber 3
88 rdf:type schema:PublicationIssue
89 N6bdb467289794c218e74cb0a246f347d schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
90 schema:name Oligopeptides
91 rdf:type schema:DefinedTerm
92 N6d81f1708fab4d9ea6ff02d10a362b73 rdf:first sg:person.01135422566.97
93 rdf:rest N0f2a0749ba6e40a7b6c8f252846b170a
94 N6de31aad88834ed1b63c7a47727f8f18 schema:name Springer Nature - SN SciGraph project
95 rdf:type schema:Organization
96 N6dea6aabba4d43c98783c84c08d321ce schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
97 schema:name Ligands
98 rdf:type schema:DefinedTerm
99 N72bd283fe1d44583927190605034f3b7 rdf:first sg:person.0703717100.51
100 rdf:rest Nb1f40ee1e5944753a4b0037ef4a2c842
101 N74fffaf6c97d4d289a8cbc7cd2a11bee schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
102 schema:name Drug Design
103 rdf:type schema:DefinedTerm
104 N78bfe0c324b441c28fd21284c872e395 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
105 schema:name Molecular Conformation
106 rdf:type schema:DefinedTerm
107 N791acb153efa400eb16b22502a84bbb0 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
108 schema:name Integrin alpha4beta1
109 rdf:type schema:DefinedTerm
110 N7f6ae8887b534840949769d7125554a6 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
111 schema:name Quantitative Structure-Activity Relationship
112 rdf:type schema:DefinedTerm
113 N8dc002cb8319444db41d860f469f34f3 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
114 schema:name Binding Sites
115 rdf:type schema:DefinedTerm
116 Na151de3fdc6f401fa597abd01ca0ee7e schema:name nlm_unique_id
117 schema:value 8710425
118 rdf:type schema:PropertyValue
119 Nb1f40ee1e5944753a4b0037ef4a2c842 rdf:first sg:person.01066260700.27
120 rdf:rest Ndbcdfda2cd544770a9006db48d0e05da
121 Nb59646a86f3c487186da2c64a5b4bf62 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
122 schema:name In Vitro Techniques
123 rdf:type schema:DefinedTerm
124 Nb66c42a1472c4e83b47fd109c7d8facf schema:name pubmed_id
125 schema:value 12363218
126 rdf:type schema:PropertyValue
127 Nbb0aed8cfe8e443ba16be392d36a6174 schema:name readcube_id
128 schema:value 8fbf133ed460174043cd46dbdb61396b7188ea7caa1f91cce40475badad6349e
129 rdf:type schema:PropertyValue
130 Nc3aa615a41e64db299fec13f7607496e rdf:first sg:person.01361471370.91
131 rdf:rest rdf:nil
132 Nc66ee9ed143945dcb921d8ed4335bdab rdf:first sg:person.01013714776.39
133 rdf:rest Ndc9a9f7c4f16414588cd76f3c91b5b8a
134 Nda8ed59b8db44a2e9b09ce3c76e94856 rdf:first sg:person.01270362723.85
135 rdf:rest N20aac324c022492fae1b89862c94f22f
136 Ndbcdfda2cd544770a9006db48d0e05da rdf:first sg:person.010077157364.71
137 rdf:rest Nc66ee9ed143945dcb921d8ed4335bdab
138 Ndc9a9f7c4f16414588cd76f3c91b5b8a rdf:first sg:person.01222236272.86
139 rdf:rest Nc3aa615a41e64db299fec13f7607496e
140 Ne06f9f18aa314b83aa7bc1f0b03af4d5 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
141 schema:name Computer-Aided Design
142 rdf:type schema:DefinedTerm
143 Ned7ea3944b4b44f7bfd10be7041c059f schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
144 schema:name Methylation
145 rdf:type schema:DefinedTerm
146 Nf3ff0b6a9aa74c7d806fea087ec02ee9 schema:name doi
147 schema:value 10.1023/a:1020130418084
148 rdf:type schema:PropertyValue
149 anzsrc-for:11 schema:inDefinedTermSet anzsrc-for:
150 schema:name Medical and Health Sciences
151 rdf:type schema:DefinedTerm
152 anzsrc-for:1107 schema:inDefinedTermSet anzsrc-for:
153 schema:name Immunology
154 rdf:type schema:DefinedTerm
155 sg:journal.1105375 schema:issn 0928-2866
156 1573-9023
157 schema:name Journal of Computer-Aided Molecular Design
158 rdf:type schema:Periodical
159 sg:person.010077157364.71 schema:affiliation https://www.grid.ac/institutes/grid.417832.b
160 schema:familyName Karpusas
161 schema:givenName Michael
162 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.010077157364.71
163 rdf:type schema:Person
164 sg:person.01013714776.39 schema:affiliation https://www.grid.ac/institutes/grid.83440.3b
165 schema:familyName Palmer
166 schema:givenName Rex
167 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01013714776.39
168 rdf:type schema:Person
169 sg:person.01020306447.41 schema:affiliation https://www.grid.ac/institutes/grid.417832.b
170 schema:familyName Singh
171 schema:givenName Juswinder
172 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01020306447.41
173 rdf:type schema:Person
174 sg:person.01066260700.27 schema:affiliation https://www.grid.ac/institutes/grid.417832.b
175 schema:familyName Hammond
176 schema:givenName Charles
177 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01066260700.27
178 rdf:type schema:Person
179 sg:person.01135422566.97 schema:affiliation https://www.grid.ac/institutes/grid.417832.b
180 schema:familyName Vlijmen
181 schema:givenName Herman van
182 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01135422566.97
183 rdf:type schema:Person
184 sg:person.01155551412.12 schema:affiliation https://www.grid.ac/institutes/grid.417832.b
185 schema:familyName Cuervo
186 schema:givenName Julio
187 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01155551412.12
188 rdf:type schema:Person
189 sg:person.01157537767.39 schema:affiliation https://www.grid.ac/institutes/grid.417832.b
190 schema:familyName Lee
191 schema:givenName Wen-Cherng
192 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01157537767.39
193 rdf:type schema:Person
194 sg:person.01222236272.86 schema:affiliation https://www.grid.ac/institutes/grid.83440.3b
195 schema:familyName Chattopadhyay
196 schema:givenName Tapan
197 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01222236272.86
198 rdf:type schema:Person
199 sg:person.01244761400.24 schema:affiliation https://www.grid.ac/institutes/grid.417832.b
200 schema:familyName Lin
201 schema:givenName Ko-Chung
202 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01244761400.24
203 rdf:type schema:Person
204 sg:person.01270362723.85 schema:affiliation https://www.grid.ac/institutes/grid.417832.b
205 schema:familyName Liao
206 schema:givenName Yusheng
207 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01270362723.85
208 rdf:type schema:Person
209 sg:person.01313074600.49 schema:affiliation https://www.grid.ac/institutes/grid.417832.b
210 schema:familyName Ateeq
211 schema:givenName Humayun
212 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01313074600.49
213 rdf:type schema:Person
214 sg:person.01361471370.91 schema:affiliation https://www.grid.ac/institutes/grid.417832.b
215 schema:familyName Adams
216 schema:givenName Steven P.
217 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01361471370.91
218 rdf:type schema:Person
219 sg:person.0703717100.51 schema:affiliation https://www.grid.ac/institutes/grid.417832.b
220 schema:familyName Zimmerman
221 schema:givenName Craig
222 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0703717100.51
223 rdf:type schema:Person
224 sg:pub.10.1038/373539a0 schema:sameAs https://app.dimensions.ai/details/publication/pub.1051713115
225 https://doi.org/10.1038/373539a0
226 rdf:type schema:CreativeWork
227 https://app.dimensions.ai/details/publication/pub.1077688636 schema:CreativeWork
228 https://app.dimensions.ai/details/publication/pub.1082391460 schema:CreativeWork
229 https://app.dimensions.ai/details/publication/pub.1082425280 schema:CreativeWork
230 https://doi.org/10.1002/9780470514719.ch13 schema:sameAs https://app.dimensions.ai/details/publication/pub.1043823658
231 rdf:type schema:CreativeWork
232 https://doi.org/10.1021/bi980311a schema:sameAs https://app.dimensions.ai/details/publication/pub.1055215592
233 rdf:type schema:CreativeWork
234 https://doi.org/10.1021/ja00226a005 schema:sameAs https://app.dimensions.ai/details/publication/pub.1055715782
235 rdf:type schema:CreativeWork
236 https://doi.org/10.1021/jm00007a003 schema:sameAs https://app.dimensions.ai/details/publication/pub.1055932355
237 rdf:type schema:CreativeWork
238 https://doi.org/10.1021/jm00077a003 schema:sameAs https://app.dimensions.ai/details/publication/pub.1055934333
239 rdf:type schema:CreativeWork
240 https://doi.org/10.1021/jm980673g schema:sameAs https://app.dimensions.ai/details/publication/pub.1055959172
241 rdf:type schema:CreativeWork
242 https://doi.org/10.1073/pnas.90.22.10494 schema:sameAs https://app.dimensions.ai/details/publication/pub.1013279571
243 rdf:type schema:CreativeWork
244 https://doi.org/10.1073/pnas.92.12.5714 schema:sameAs https://app.dimensions.ai/details/publication/pub.1005946835
245 rdf:type schema:CreativeWork
246 https://doi.org/10.1083/jcb.125.6.1395 schema:sameAs https://app.dimensions.ai/details/publication/pub.1051217174
247 rdf:type schema:CreativeWork
248 https://doi.org/10.1159/000237468 schema:sameAs https://app.dimensions.ai/details/publication/pub.1038691915
249 rdf:type schema:CreativeWork
250 https://doi.org/10.1172/jci116575 schema:sameAs https://app.dimensions.ai/details/publication/pub.1046310997
251 rdf:type schema:CreativeWork
252 https://doi.org/10.1172/jci117032 schema:sameAs https://app.dimensions.ai/details/publication/pub.1003779133
253 rdf:type schema:CreativeWork
254 https://doi.org/10.1172/jci117962 schema:sameAs https://app.dimensions.ai/details/publication/pub.1009515471
255 rdf:type schema:CreativeWork
256 https://doi.org/10.1172/jci119571 schema:sameAs https://app.dimensions.ai/details/publication/pub.1014773540
257 rdf:type schema:CreativeWork
258 https://doi.org/10.2337/diab.43.4.529 schema:sameAs https://app.dimensions.ai/details/publication/pub.1070737298
259 rdf:type schema:CreativeWork
260 https://doi.org/10.3109/15419069509081293 schema:sameAs https://app.dimensions.ai/details/publication/pub.1036241044
261 rdf:type schema:CreativeWork
262 https://doi.org/10.3233/hab-1997-8102 schema:sameAs https://app.dimensions.ai/details/publication/pub.1083133275
263 rdf:type schema:CreativeWork
264 https://www.grid.ac/institutes/grid.417832.b schema:alternateName Biogen (United States)
265 schema:name Biogen Inc, 12 Cambridge Center, MA02142, Cambridge, USA
266 rdf:type schema:Organization
267 https://www.grid.ac/institutes/grid.83440.3b schema:alternateName University College London
268 schema:name Dept. of Crystallography, Birkbeck College, University of London, Malet Street, WC1E 7HX, London, U.K
269 rdf:type schema:Organization
 




Preview window. Press ESC to close (or click here)


...