Document Report Card

ID: ALA3217645

Journal: Medchemcomm

Title: Online parallel fragment screening and rapid hit exploration for nicotinic acetylcholine receptors.

Authors: de Kloe GE, Kool J, val Elk R, van Muijlwijk-Koezen JE, Smit AB, Lingeman H, Irth H, Niellsen WMA, de Esch JP.

Abstract: An online bioaffinity analysis system was used to screen our in-house fragment library on two related proteins, Ls- and Ac-AChBP, model proteins for nAChRs, in particular the alpha7 subtype. An efficient protocol for medium throughput fragment screening, hit validation and affinity ranking after single concentration injections was developed. The screening of the fragment library and the good correlation between online estimated pKi values (derived from a single injection) and pKi values measured with a radioligand binding assay (RBA, full range concentration curve) have proven the value of the online fluorescence enhancement assay in FBDD. The online bioaffinity system was also used for rapid hit exploration using single point injections of combinatorial libraries at 96-well format. This led to the discovery of an optimized hit with micromolar affinity towards the alpha7 nAChR.

DOI: 10.1039/C1MD00031D