Limits...
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 interaction of inhibitor Laur-DArg-DPhe-OMe with a whole hydrophobic cage without its sub-division on pockets.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2627521&req=5

Figure 4: Schematic representation of interaction of inhibitor Laur-DArg-DPhe-OMe with a whole hydrophobic cage without its sub-division on pockets.

Mentions: Argatroban has hydrophobic moieties that bind in the hydrophobic “P-pocket” and the “D-pocket, and a guanidinium moiety that binds in the specificity pocket and forms a salt bridge with the carboxyl group of Asp 189. “P-pocket” and “D-pocket as used by Banner and Hadvary (Banner J Biol Chem 1991) [36]. The Tyr60A-Pro60B-Pro60C-Trp-60D loop creates with Trp215. Leu99, and Ile174 a double hydrophobis pocket which they have divided into the P-pocket (Proximal to the active site serine) and a D-pocket (distal to the active site serine. Nevertheless, we consider that through the absent of X-ray data of the thrombin complexes with inhibitors containing in its structure fatty acid moiety it will be correct to consider the interaction of our new inhibitor with a whole hydrophobic cage without its division on pockets, as it is shown in Fig. (4).


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 interaction of inhibitor Laur-DArg-DPhe-OMe with a whole hydrophobic cage without its sub-division on pockets.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Schematic representation of interaction of inhibitor Laur-DArg-DPhe-OMe with a whole hydrophobic cage without its sub-division on pockets.
Mentions: Argatroban has hydrophobic moieties that bind in the hydrophobic “P-pocket” and the “D-pocket, and a guanidinium moiety that binds in the specificity pocket and forms a salt bridge with the carboxyl group of Asp 189. “P-pocket” and “D-pocket as used by Banner and Hadvary (Banner J Biol Chem 1991) [36]. The Tyr60A-Pro60B-Pro60C-Trp-60D loop creates with Trp215. Leu99, and Ile174 a double hydrophobis pocket which they have divided into the P-pocket (Proximal to the active site serine) and a D-pocket (distal to the active site serine. Nevertheless, we consider that through the absent of X-ray data of the thrombin complexes with inhibitors containing in its structure fatty acid moiety it will be correct to consider the interaction of our new inhibitor with a whole hydrophobic cage without its division on pockets, as it is shown in Fig. (4).

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