Computational analysis of non-competitive antagonist arylguanidine-α7 nAChR complexes.

Osama I Alwassil, Galya R Abdrakhmanova, Małgorzata Dukat

Journal of molecular graphics & modelling 2021 Sep

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meta-Chlorophenylguanidine (1) is a non-competitive α7 nicotinic acetylcholine receptor (nAChR) antagonist. Here we examined the hydrogen bond donor role of the anilinic N1-H on the inhibitory effect of 1 by preparing its N1-CH3 counterpart 2. Analog 2 was found to be at least as potent as 1 as a non-competitive α7 nAChR antagonist in a patch-clamp assay. To establish a structural basis for the mode of interaction of guanidines 1 and 2, we generated 100 homology models of the hα7 nAChR. This was followed by Connolly surface (SYBYL-X2.1) and blind docking (AutoDock 4.1) studies to identify eight possible binding pockets, two of which were supported by empirical data and employed in our docking studies. The optimized model-ligand complexes were analyzed using a Hydropathic INTeractions (HINT) analysis in order to compare and contrast different binding pockets and modes. We identified a potential allosteric binding site and distinct rotameric binding modes for 1 and 2 at α7 nAChRs. These differences in the binding orientations minimized the importance of an anilinic NH function for the antagonist activity at nACh receptors. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Osama I Alwassil, Galya R Abdrakhmanova, Małgorzata Dukat. Computational analysis of non-competitive antagonist arylguanidine-α7 nAChR complexes. Journal of molecular graphics & modelling. 2021 Sep;107:107943