Synthesis, biological evaluation, X-ray molecular structure and molecular docking studies of RGD mimetics containing 6-amino-2,3-dihydroisoindolin-1-one fragment as ligands of integrin αIIbβ3

Andrei A Krysko,Georgiy V Samoylenko,Pavel G Polishchuk,Marina S Fonari,Victor Ch Kravtsov,Sergei A Andronati,Tatyana A Kabanova,Janusz Lipkowski,Tetiana M Khristova,Victor E Kuz’Min,Vladimir M Kabanov,Olga L Krysko,Alexandre A Varnek

doi:10.1016/j.bmc.2013.05.019

Abstract

A series of novel RGD mimetics containing phthalimidine fragment was designed and synthesized. Their antiaggregative activity determined by Born’s method was shown to be due to inhibition of fibrinogen binding to αIIbβ3. Molecular docking of RGD mimetics to αIIbβ3 receptor showed the key interactions in this complex, and also some correlations have been observed between values of biological activity and docking scores. The single crystal X-ray data were obtained for five mimetics.

Highlights

Thrombosis is the most important pathological process underlying many cardiovascular diseases, which are responsible for elevated mortality worldwide.[1]
It gave a stimulus to the development of an entirely separate class of antiplatelet drugs - fibrinogen receptor antagonists
It has been demonstrated that RGD mimetics containing 2,3-dihydroisoindol-1-one can be effificiently used as aIIbb[3] antagonists and platelet aggregation inhibitors through appropriate structural modulation

Summary

Introduction

Thrombosis is the most important pathological process underlying many cardiovascular diseases, which are responsible for elevated mortality worldwide.[1]. During the platelet activation process, the surface of the platelet transforms its shape to expose the fibrinogen receptors. These receptors bind to fibrinogen and Von Willebrand factor, resulting in clot formation and clot adherence, respectively.[2] Binding of fibrinogen to aIIbb[3] on platelets is responsible for securing aggregated platelets to one another.

Methods

Results

Conclusion