3D QSAR based design of novel substituted urea molecules as heparanase inhibitors

Abstract

Aim

To study the key pharmacophore requirements for heparanase inhibition and design of new molecules.

Method

Three dimensional quantitative structure activity relationship (3D QSAR) methodologies namely Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were applied, PLS analysis was performed and QSAR models were generated for a set of 43 bezoxazol-5-yl acetic acid derivatives and 1,3-bis[4-(1H-bezimidazol-2-yl)-phenyl urea reported as potent inhibitors of heparanase.

Result

QSAR model showed good internal and external statistical reliability that is evident from the $q_{\text{loo}}^2$, $r_{\text{ncv}}^2$ and $r_{\text{pred}}^2$. CoMFA model provides a correlation of steric and electrostatic field with biological activities. CoMSIA model provides a correlation of steric, electrostatic, acceptor, donor and hydrophobic fields with biological activities.

Conclusion

The identified key features enabled us to design novel symmetrical 1,3-bis[4-(1H-bezimidazol-2-yl)-phenyl urea derivatives.