[Design and activity determination of small molecular inhibitors of integrin alphavbeta3].
OBJECTIVE
To explore the design and activity determination of small molecular inhibitors of integrin alphavbeta3 through structure-based virtual screening.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Ji
Qing
Q
State Key Laboratory of Hematology, Institute of Hematology, CAMS and PUMC, Tianjin 300020, China.
Zhou
Yuan
Y
Peng
Hui
H
Huang
Niu
N
Qi
Jing
J
Xiong
Dong-sheng
DS
Gao
Ying-dai
YD
Yang
Ming
M
Yang
Chun-zheng
CZ
D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D057166:High-Throughput Screening Assays; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018919:Neovascularization, Physiologic / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology
D039302:Integrin alphaVbeta3