By employing in silico structure‐based design approaches, novel hexapeptides, pentapeptides and tetrapeptides were designed, new compounds that may be used as additives in the treatment of acute coronary diseases (ACD). Additionally, these new compounds were further tested for their ability to reversible inhibit alpha thrombin using kinetics, thermodynamics, and platelets aggregation assays. Initial molecular docking experiments generated a candidate group of compounds with both L‐ and D‐ amino acids, including two classes of sequence spaces: 1‐D‐Phe(P3)‐Pro(P2)‐Arg(P1)‐D‐Pro(P1′)‐P2′‐P3′‐CONH2 and 2‐D‐Phe(P3)‐Pro(P2)‐D‐Arg(P1)‐P1′‐P2′‐P3′‐CONH2. D‐Pro and D‐Arg replaced Arg in the P1′ and P1 positions, respectively, increasing the stability to proteolysis of the designed peptides. The newly‐designed peptides competitively inhibited the alpha‐thrombin induced cleavage of a chromogenic substrate, at 1,050‐0.8 uM. Additionally, some lead compounds inhibited the thrombin‐activated human platelets aggregation in the presence of its natural substrate, fibrinogen, effectively sustaining these peptides as powerful new anti‐coagulants. Molecular docking experiments suggest a model for achieving favorable hydrogen bonding interactions between the new peptides and thrombin, and provide a rationale for the development of a new series of anticoagulant drugs.
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