Studies of tricyclic piperazine/piperidine furnished molecules as novel integrin αvβ3/αIIbβ3 dual antagonists using 3D-QSAR and molecular docking

The development of injectable integrin αvβ3/αIIbβ3 dual antagonists attracts much attention of research for treating of acute ischemic diseases in recent years. In this work, based on a dataset composed of 102 tricyclic piperazine/piperidine furnished dual αvβ3 and αIIbβ3 antagonists, a variety of in silico modeling approaches including the comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), and molecular docking were applied to reveal the requisite 3D structural features impacting the biological activities. Our statistical results show that the ligand-based 3D-QSAR models for both the αvβ3 and αIIbβ3 studies exhibited satisfactory internal and external predictability, i.e., for the CoMFA models, results of Q2 = 0.48, Rncv2=0.87, Rpred2=0.71 for αvβ3 and Q2 = 0.50, Rncv2=0.85, Rpred2=0.72 for αIIbβ3 analysis were obtained, and for the CoMSIA ones, the outcomes of Q2 = 0.55, Rncv2=0.90, Rpred2=0.72 for αvβ3 and Q2 = 0.52, Rncv2=0.88, Rpred2=0.74 for αIIbβ3 were achieved respectively. In addition, through a comparison between 3D-QSAR contour maps and docking results, it is revealed that that the most crucial interactions occurring between the tricyclic piperazine/piperidine derivatives and αvβ3/αIIbβ3 receptor ligand binding pocket are H-bonding, and the key amino acids impacting the interactions are Arg214, Asn215, Ser123, and Lys253 for αvβ3, but Arg214, Asn215, Ser123 and Tyr190 for αIIbβ3 receptors, respectively. Halogen-containing groups at position 15 and 16, benzene sulfonamide substituent at position 23, and the replacement of piperazine with 4-aminopiperidine of ring B may increase the αvβ3/αIIbβ3 antagonistic activity. The potencies for antagonists to inhibit isolated αvβ3 and αIIbβ3 are linear correlated, indicating that similar interaction mechanisms may exist for the series of molecules. To our best knowledge this is the first report on 3D-QSAR modeling of these dual αvβ3/αIIbβ3 antagonists. The results obtained should provide information for better understanding of the mechanism of antagonism and thus be helpful in design of novel potent dual αvβ3/αIIbβ3 antagonists.

.Figure optionsDownload high-quality image (440 K)Download as PowerPoint slideResearch highlights▶ H-bond properties play crucial roles for both αvβ3 and αIIbβ3 antagonistic activity. ▶ Key amino acids impacting the receptor-ligand interactions are Arg214, Asn215, Ser123, and Lys253 for αvβ3, but Arg214, Asn215, Ser123 and Tyr190 for αIIbβ3 receptors, respectively. ▶ Halogen-containing groups at position 15 and 16, benzene sulfonamide substituent at position 23, and the replacement of piperazine with 4-aminopiperidine of ring B may increase the αvβ3/αIIbβ3 antagonistic activity.