Biophysical techniques that enable the screening and identification of weak affinity fragments against a target protein are at the heart of Fragment Based Drug Design approaches. In the case of membrane proteins, the crucial criteria for fragment screening are low protein consumption, unbiased conformational states and rapidity because of the difficulties in obtaining sufficient amounts of stable and functionally folded proteins. Here we show for the first time that lipidnanodisc systems (membrane-mimicking environment) and ultra-miniaturized affinity chromatography can be combined to identify specific small molecule ligands that bind to an integral membrane protein. The approach is exemplified using the AA2AR GPCR. Home-made affinity nano-columns modified with nanodiscs-embedded AA2AR (only about 1 µg of protein per column) are fully characterized by frontal chromatographic experiments. This method allows (i) to distinguish specific and unspecific ligand/receptor interactions, (ii) to assess dissociation constants, (iii) to identify the binding pocket of uncharacterized ligands using a reference compound with competition experiments. Weak affinity ligands with Kd in the low to high micromolar range be detected. At last, the applicability of this method is demonstrated with 6 fragments recently identified as ligands or non-ligands of AA2AR.