Design and activity determination of small molecular inhibitors of integrin alphavbeta3 / 中国医学科学院学报
Acta Academiae Medicinae Sinicae
;
(6): 347-352, 2007.
Article
in Chinese
| WPRIM
| ID: wpr-229976
ABSTRACT
<p><b>OBJECTIVE</b>To explore the design and activity determination of small molecular inhibitors of integrin alphavbeta3 through structure-based virtual screening.</p><p><b>METHODS</b>Based on the crystal structure of integrin ctv33 extracellular segment in complex with an ARG-GLY-ASP ligand, docking procedure against the receptor binding domain was performed on 3D database. Integrin alphavbeta3-mediated cell adhesion assay was performed to assess the adhesion-inhibiting ability of the candidate compounds. Cell migration assay and capillary-structure-like formation inhibition assay were used to estimate the effects of the compounds on integrin alphavbeta3. Analysis of molecular graphics was carried out to deduce a probable binding model of compound with integrin alphavbeta3.</p><p><b>RESULTS</b>From the top 1000 compounds with the best DOCK energy score, 50 compounds were selected for biological assay based on chemical and drug-like diversity. Seven of 50 compounds showed notable inhibition activity on cell adhesion, and two with half-maximum inhibition concentration (IC50) values less than 100 mol/L. The compound with best activity (1-37) showed high inhibitory activity in cell migration assay and capillary-structure-like formation inhibition assay. Molecular graphics analysis indicated that metal ion-dependent adhesion site (MIDAS) might be involved in the compound 1-37-mediated inhibition of ligand binding with integrin alphavbeta3.</p><p><b>CONCLUSIONS</b>Through virtual screening combined with biological assay, a promising lead compound was discovered to inhibit integrin alphavbeta3, which embodies the rational drug design with computation aid and brings a new thought and approach to find novel inhibitors of integrin.</p>
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Physiology
/
Umbilical Veins
/
Cell Adhesion
/
Cell Movement
/
Cells, Cultured
/
Chemistry
/
Neovascularization, Physiologic
/
Quantitative Structure-Activity Relationship
/
Cell Biology
/
Integrin alphaVbeta3
Type of study:
Prognostic study
Limits:
Humans
Language:
Chinese
Journal:
Acta Academiae Medicinae Sinicae
Year:
2007
Type:
Article
Similar
MEDLINE
...
LILACS
LIS