Molecular recognition binding sites that specifically identify a target molecule are essential for research in the life sciences, clinical diagnoses and therapeutic development. Corona Phase Molecular Recognition is a technique introduced to generate synthetic recognition at the surface of a nanoparticle corona, but it remains an important question whether such entities can achieve the specificity of natural enzymes and receptors. In this work, we generate and screen a library of 24 amphiphilic polymers based on functional monomers including methacrylic acid, acrylic acid, styrene and so on, iterating upon a poly(methacrylic acid-co-styrene) motif that demonstrates a binding specificity remarkably similar to an enzyme - Phosphodiesterase Type 5 - in its molecular recognition. The corona phase binds selectively to an inhibitor - Vardenafil, as well as its derivatives, but not to another inhibitor and substrate that interact differently with the enzyme. Our study examines the specificity and sensitivity by mutation of the polymer structure and configuration, as well as the competition with native binding sites. We demonstrate that the recognition originates from the unique three-dimensional configuration of the corona phase. This work conclusively shows that corona phase molecular recognition can mimic key aspects of biological recognition sites and drug targets, opening up possibilities for new pharmaceutical and biological applications.