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Influence of aromatic and aliphatic moieties on thrombin inhibitors potency.

Poyarkov A, Rocabayera X, Poyarkova S, Kukhar V - Open Biochem J (2008)

Bottom Line: The analysis of the inhibition effect of the peptide with retro-D-sequence modified by residues of natural organic compounds (chromone or fatty acid moiety) has demonstrated that modification with the fatty acid residue appeared to be the most successful one.Introduction of lauric acid residue (Ki = 1,76 muM) maximally increased the inhibition effect.These findings establish an important role of fatty moiety in structure of inhibitors in preferential binding and inhibition of thrombin active side.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioorganic Chemistry and Petrochemistry of the Ukrainian National Academy of Sciences., 1, Murmanska St., Kiev 94, 02660, Ukraine.

ABSTRACT
Thrombin is a plasma serine protease that plays a key role in coagulation and hemostasis but also in thromboembolic diseases. Direct thrombin inhibitors could be beneficial for future anticoagulant therapy in the prophylaxis of venous and arterial thrombosis as well as myocardial infarction. To design the efficient thrombin inhibitors we have synthesized and studied peptide-based inhibitors resistant to enzymatic degradation. Compounds with general formula X-DArg-D-Phe-OMe, where X = residue of 3-[6-ethyl-7-hydroxy-3-(4-methyl-thiazol-2-yl)-4-oxo-4H-chromen-2-yl]-propionic acid (chromone) and lauric acid were synthesized by classic methods of peptides synthesis in solution. The comparative inhibitory analysis of prepared compounds in relation to thrombin was conducted. The analysis of the inhibition effect of the peptide with retro-D-sequence modified by residues of natural organic compounds (chromone or fatty acid moiety) has demonstrated that modification with the fatty acid residue appeared to be the most successful one. Introduction of lauric acid residue (Ki = 1,76 muM) maximally increased the inhibition effect. These findings establish an important role of fatty moiety in structure of inhibitors in preferential binding and inhibition of thrombin active side.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the binding mode of argatroban (MD 805) (a), and Laur-DArg-DPhe-OMe (b) to the active site of thrombin according to (Lau, Bioorg. Med. Chem. 1995)[35].
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Figure 3: Schematic representation of the binding mode of argatroban (MD 805) (a), and Laur-DArg-DPhe-OMe (b) to the active site of thrombin according to (Lau, Bioorg. Med. Chem. 1995)[35].

Mentions: Taking into account that a length of synthesized peptides is limited by two amino acid residues and they have not rigid conformation, it seems logical to assume that the fatty tail of lauric acid appears engaged in cooperation with D-phenylalanine through the hydrophobic effect and located in the «hydrophobic cage» of the secondary binding site of thrombin. The authors of the article (Lau Bioorg. Med. Chem. 1995) [35] make a schematic diagram of active site showing key binding features of thrombin. In comparison the binding of our compounds with the known anticoagulant agratroban, we used this scheme to illustrate the occupation of the Laur-D-Arg-D-Phe-OMe in the active site of thrombin as it is shown in Fig. (3).


Influence of aromatic and aliphatic moieties on thrombin inhibitors potency.

Poyarkov A, Rocabayera X, Poyarkova S, Kukhar V - Open Biochem J (2008)

Schematic representation of the binding mode of argatroban (MD 805) (a), and Laur-DArg-DPhe-OMe (b) to the active site of thrombin according to (Lau, Bioorg. Med. Chem. 1995)[35].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2627521&req=5

Figure 3: Schematic representation of the binding mode of argatroban (MD 805) (a), and Laur-DArg-DPhe-OMe (b) to the active site of thrombin according to (Lau, Bioorg. Med. Chem. 1995)[35].
Mentions: Taking into account that a length of synthesized peptides is limited by two amino acid residues and they have not rigid conformation, it seems logical to assume that the fatty tail of lauric acid appears engaged in cooperation with D-phenylalanine through the hydrophobic effect and located in the «hydrophobic cage» of the secondary binding site of thrombin. The authors of the article (Lau Bioorg. Med. Chem. 1995) [35] make a schematic diagram of active site showing key binding features of thrombin. In comparison the binding of our compounds with the known anticoagulant agratroban, we used this scheme to illustrate the occupation of the Laur-D-Arg-D-Phe-OMe in the active site of thrombin as it is shown in Fig. (3).

Bottom Line: The analysis of the inhibition effect of the peptide with retro-D-sequence modified by residues of natural organic compounds (chromone or fatty acid moiety) has demonstrated that modification with the fatty acid residue appeared to be the most successful one.Introduction of lauric acid residue (Ki = 1,76 muM) maximally increased the inhibition effect.These findings establish an important role of fatty moiety in structure of inhibitors in preferential binding and inhibition of thrombin active side.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioorganic Chemistry and Petrochemistry of the Ukrainian National Academy of Sciences., 1, Murmanska St., Kiev 94, 02660, Ukraine.

ABSTRACT
Thrombin is a plasma serine protease that plays a key role in coagulation and hemostasis but also in thromboembolic diseases. Direct thrombin inhibitors could be beneficial for future anticoagulant therapy in the prophylaxis of venous and arterial thrombosis as well as myocardial infarction. To design the efficient thrombin inhibitors we have synthesized and studied peptide-based inhibitors resistant to enzymatic degradation. Compounds with general formula X-DArg-D-Phe-OMe, where X = residue of 3-[6-ethyl-7-hydroxy-3-(4-methyl-thiazol-2-yl)-4-oxo-4H-chromen-2-yl]-propionic acid (chromone) and lauric acid were synthesized by classic methods of peptides synthesis in solution. The comparative inhibitory analysis of prepared compounds in relation to thrombin was conducted. The analysis of the inhibition effect of the peptide with retro-D-sequence modified by residues of natural organic compounds (chromone or fatty acid moiety) has demonstrated that modification with the fatty acid residue appeared to be the most successful one. Introduction of lauric acid residue (Ki = 1,76 muM) maximally increased the inhibition effect. These findings establish an important role of fatty moiety in structure of inhibitors in preferential binding and inhibition of thrombin active side.

No MeSH data available.


Related in: MedlinePlus