The pharmacophore model of PDE5 usually consists of one hydrogen bond acceptor, one hydrophobic aliphatic carbon chain and two aromatic rings. Small hydrophobic pocket and H-loop of PDE5 enzyme are important for binding affinity of PDE5 inhibitors. As well as positional and conformational changes are observed upon inhibitor binding in many cases.
The active site of PDE5 is located at a helical bundle domain at the center of C domain (catalytic domain). The substrate pocket is composed of four subsites: M site (metal-binding site), Q pocket (core pocket), H pocket (hydrophobic pocket) and L region (lid region) as demonstrated in [https://commons.wikimedia.org/wiki/File:Figure_3._PDE5_Domains.png figure 3].  The Q pocket accommodates the pyrazolopyrimidinone group of sildenafil. That suggest that other chemicals similar to guanidine groups of cGMP can also bind at this region. The amino acids residues, Gln817, Phe820, Val782 and Tyr612, are lined in the Q pocket, they are highly conserved in all PDEs. The amide moiety of the pyrazolopyrimidinone group forms a bidentate hydrogen bond with the ɣ-amide group of Gln817. 3D structure of sildenafil is demonstrated in [https://commons.wikimedia.org/wiki/File:3D.Sild.2.png figure 4].