DTIs that fit in the active binding site have to fit in the hydrophobic pocket (S1) that contains aspartic acid residue at the bottom which recognizes the basic side chain. The S2 site has a loop around tryptophan which occludes a hydrophobic pocket that can recognize larger aliphatic residues. The S3 site is flat and the S4 site is hydrophobic, it has tryptophan lined by leucine and isoleucine.
Nα-(2-naphthyl-sulphonyl-glycyl)-DL-p-amidinophenylalanyl-piperidine (NAPAP) binds thrombin in the S1, S2 and S4 pockets. The amidine group on NAPAP forms a bidentate salt bridge with Asp deep in the S1 pocket, the piperidine group takes the role of proline residue and binds in the S2 pocket, and the naphthyl rings of the molecule forms a hydrophobic interaction with Trp in the S4 pocket. Pharmaceutical companies have used the structural knowledge of NAPAP to develop DTIs. Dabigatran, like NAPAP binds to S1, S2 and S4 pockets. Benzamidine group on the dabigatran structure binds deep in the S1 pocket, the methylbenzimidazole fits nicely in the hydrophobic S2 pocket and the Ile and Leu at the bottom of the S4 pocket binds to the aromatic group of dabigatran.