Molecualr modelling studies on alpha-7 nicotinic receptor allosteric modulators yields novel filter-based virtual screening protocol

Jul 02, 2019

DOI: 10.1016/j.jmgm.2019.07.001

Published in: Journal of Molecular Graphics and Modelling

Publisher: Elsevier

Sarah Al Rawashdah Amar hamrouni

The ɑ7 receptor is a member in the nicotinic acetylcholine receptor (nAChR) which has been implicated in several neurological disorders. Beside normal agonists and antagonists of α7 nAChRs, several studies revealed other types of molecules that are able to activate or deactivate ɑ7 receptors via allosteric binding; those are called positive allosteric modulators (PAMs) or negative allosteric modulators (NAMs), with the former having more pharmacological importance than the latter. Since both types of modulators are believed to bind to the same place in the intracavity of the transmembrane domain, it was important to differentiate between them in terms of structural features and their binding with the target receptor, and then use these specific characteristics as filters to discriminate PAMs from NAMS. To do that, modulators' physicochemical properties were investigated using two databases of known PAMs or NAMs which were then used to elucidate a specific pharmacophore for each class. Interestingly, PAMs were found to be relatively larger and more polar compared to NAMs, which was observed to carry a positive charge with double the number of cases than PAMs. Furthermore. a pharmacophore for each class was developed and the best PAMs pharmacophore was successfully able to pass 94% of tested PAMs and to eliminate 71% of NAMs, while the best NAM pharmacophore was able to pass 82% of NAMs and to filter out 85% of PAMs. Docking these known modulators into the α7 nAChRs allosteric site identified several amino acids that are key for specifically binding PAMs compared to NAMs. Next, these findings were employed in virtual screening and then seeding experiments were conducted to validate the developed pharmacophores usage as filters prior to the final docking. Interestingly, the number of retrieved PAMs in the final docking list was improved by up to five-fold compared to the non-filtered protocol, which clearly indicates for the efficiency of our protocol to pick true PAMs over decoys. Hence, the pharmacophore-based filtering technique developed in this work can act as a valuable tool in the pursuit of new, potent PAM molecules as therapeutically useful modulators of the α7 nicotinic receptors.

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