Determination of structural requirements of influenza neuraminidase type A inhibitors and binding interaction analysis with the active site of A/H1N1 by 3D-QSAR CoMFA and CoMSIA modeling

Abstract

As a basis for predicting structural features that may lead to the design of more potent and selective inhibitors of influenza neuraminidase type A, three-dimensional quantitative structure–activity relation (3D-QSAR) studies were performed on a set of sixty one known neuraminidase type A inhibitors. The studies include Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Atom and centroid/atom based alignment and docked conformation-based alignments were used to develop different CoMFA models. A homology modelled A/H1N1 with one of the most active neuraminidase inhibitors (Relenza) inside the active site structure was used for docking purposes. The resulted docking based conformers of the inhibitors were used for developing the CoMFA model. The model developed by considering the docked conformation-based alignment was found to perform better than that developed by atom and centroid/atom based alignments with excellent predictive r². The CoMFA model generated using docked conformer-based alignment served as alignment strategy for CoMSIA. The CoMSIA model with a combination of steric, electrostatic and acceptor fields yielded the highest cross-validated r². CoMFA steric, electrostatic and CoMSIA donor contour maps were mapped in the active site of A/H1N1. These 3D-QSAR studies revealed indispensable structural features of different chemical classes of molecules which could be exploited for the structural modifications of these lead molecules in order to achieve improved neuraminidase type A inhibitory activity.