Center for Hemostasis and Thrombosis

Bratislava, Slovakia

Center for Hemostasis and Thrombosis

Bratislava, Slovakia
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Remko M.,Comenius University | Remko M.,Center for Hemostasis and Thrombosis | Duijnen P.T.V.,Zernike Institute for Advanced Materials | Broer R.,Zernike Institute for Advanced Materials
RSC Advances | Year: 2013

Our work reports in detail the results of systematic large-scale theoretical investigations of the complexes modeling heparin-protein interaction (CH3OSO3 -⋯Arg+, CH 3NHSO3 -⋯Arg+, CH 3CO2 -⋯Arg+, CH 3OSO3 -⋯Lys+, CH 3NHSO3 -⋯Lys+, CH 3CO2 -⋯Lys+, CH 3OPO3H2-⋯Arg+, CH 3OPO3H2-⋯Lys+, CH 3O(CH3)PO2 -⋯Arg+, CH3O(CH3)PO2 -⋯Lys +, 1,4-DiOMeIdoA2SNa-⋯Arg+, 1,4-DiOMeIdoA2SNa-⋯Lys+) using Becke3LYP and B97D levels of the density functional theory, as well as at MP2 ab initio method. Although initial geometries of complexes paired anionic and cationic species (ionic hydrogen bonds), full geometry optimization of isolated systems resulted in several cases with relaxed geometry and complexes stabilized via neutral hydrogen bonds. Hydration caused appreciable geometry changes, especially for substituents (carboxylate and sulphate groups) of the saccharidic part of the complex. The computed Gibbs energies ΔG° of the ionic hydrogen bond systems are negative and high (from -340 to -450 kJ mol-1). In complexes with neutral H-bonds the large destabilizing effect of entropy drives the association reaction to the left. However, owing to a sufficient enthalpy change Gibbs energies are indeed negative, but small (from -20 to 0 kJ mol -1) and the tendency to associate in gas-phase for the complex CH3OPO3H-⋯Lys+ is negligible. The phosphate anion in its complexes with arginine and lysine proved the lowest tendency to associate. Displacing of Na+ ions from heparine binding sites by protonated arginine and lysine molecules resulted in positive reaction energies. Solvent (water) reversed the reactivity. Reaction energies computed for the reactions conducted in water are calculated negative, i.e. water drives these reactions to the right. © 2012 The Royal Society of Chemistry.


Remko M.,Comenius University | Remko M.,Center for Hemostasis and Thrombosis | Van Duijnen P.T.,Zernike Institute for Advanced Materials | Broer R.,Zernike Institute for Advanced Materials
RSC Advances | Year: 2013

The effects of complexation by Li+, Na+, K +, Mg2+, and Ca2+ counterions and water on the molecular structure of the Fondaparinux pentameter (D-E-F-G-H) and its dimer units (D-E, E-F, F-G and G-H) are studied using Becke 3LYP hybrid density functional theory and molecular modeling. The ionic charge state, the number of metal ion adducts and the counterion radii are important factors that influence counterion-induced conformational changes in these pentamers and dimers of heparin. The displacement of the Li+, Na+, K+, Mg2+ and Ca2+ cations from their binding sites in the salts results in appreciable changes in the anion conformations. The interaction energies are very negative and span a broad range from -1900 to -16000 kJ mol-1, which is the result of multiple coordinate bonds between ions and basic centers in glycosaminoglycan units. © 2013 The Royal Society of Chemistry.


Remko M.,Comenius University | Remko M.,Center for Hemostasis and Thrombosis | Broer R.,Zernike Institute for Advanced Materials | Van Duijnen P.T.,Zernike Institute for Advanced Materials
Chemical Physics Letters | Year: 2013

Density functional theory methods with the B3LYP functional have been used to letter the acidity of carboxyl, O-sulfo and N-sulfo groups in six basic monomeric structural units of heparin (1-OMe ΔUA-2S, 1-OMe GlcN-S6S, 1,4-DiOMe GlcA, 1,4-DiOMe GlcN-S3S6S, 1,4-DiOMe IdoA-2S, and 1,4-DiOMe GlcN-S6S). The predicted gas-phase acidity of the acidic functional groups in the monomeric structural units of heparin is: O-sulfo > N-sulfo > carboxyl. The computed pKa values provide the same order of acidity as was observed in water solution. This implies that hydration does not change ordering of acidity of major acidic groups of monomeric structural units of heparin. © 2013 Elsevier B.V. All rights reserved.


Remko M.,Comenius University | Broer R.,Zernike Institute for Advanced Materials | Remkova A.,Center for Hemostasis and Thrombosis | Van Duijnen P.T.,Zernike Institute for Advanced Materials
Chemical Physics Letters | Year: 2014

Density functional theory methods with the B3LYP and B97D functionals with triple-zeta 6-311++G(d,p) basis set have been used to study the acidity, basicity and metal affinity of l-γ-carboxyglutamic acid (GLA) and its peptide derivative [2-acetylamino-3-(methylamino)-3-oxopropyl]malonic acid (AMD-GLA). The Gibbs interaction energies of the GLA2-...M2+ and AMD-GLA2-...M2+ (M = Mg, Ca, Zn) complexes show an increasing binding affinity in the order Ca2+ < Mg2+ < Zn2+ The transition metal Zn2+ is most effectively recognized by the dianions of GLA and AMD-GLA. Of the dianions studied the AMD-GLA dianion is the strongest Lewis base. Computations that include the effect of solvation showed that in water the relative stability of GLA2-...M2+ and AMD-GLA2-...M2+ ionic bonds is rapidly diminished. The computed interaction Gibbs energy in water is small and negative. © 2014 Published by Elsevier B.V.


Remko M.,Comenius University | Remko M.,Center for Hemostasis and Thrombosis | Broer R.,Zernike Institute for Advanced Materials | Remkova A.,Center for Hemostasis and Thrombosis
RSC Advances | Year: 2014

The methods of computational chemistry have been used to elucidate the molecular properties of coumarinic anticoagulants (acenocoumarol, phenprocoumon, warfarin and tecarfarin) and direct thrombin inhibitors (melagatran, dabigatran and their prodrug forms, ximelagatran and dabigatran etexilate). The geometries and energies of these drugs have been computed at the Becke3LYP/6-311++G(d,p) level of theory. In the case of the vitamin K antagonists (acenocoumarol, phenprocoumon, warfarin and tecarfarin), the most stable tautomer in both the gas-phase and water solution is tautomer A, which contains the 4-hydroxycoumarin moiety. The R(+)-enantiomer of this tautomer is the most stable structure in warfarin and acetocoumarol. For phenprocoumon, the S(-)-enantiomer was the most stable species. The computed dissociation constants show that these drugs are almost completely ionized at physiological pH = 7.4. Tecarfarin is the vitamin K antagonist with the highest lipophilicity. The prodrugs ximelagatran and dabigatran etexilate are described as lipophilic drugs. The prodrugs' metabolites, melagatran and dabigatran, are substantially less lipophilic. The relatively high polar surface area value of acenocoumarol (113.3) results in lessened absorption in comparison with warfarin. Phenprocoumon, with PSA value 50.4, had the highest calculated absorption of all of the anticoagulants in the study. The direct thrombin inhibitors, melagatran and dabigatran, have a high total number of proton donor and proton acceptor groups (15), a high PSA (150) and the lowest absorption of the drugs studied. © 2014 The Royal Society of Chemistry.


Remko M.,Comenius University | Broer R.,Zernike Institute for Advanced Materials | Remkova A.,Center for Hemostasis and Thrombosis | Van Duijnen P.T.,Zernike Institute for Advanced Materials
Chemical Physics Letters | Year: 2015

The formation of the calcium and zinc salts from CaCl2, ZnCl2 and six monomeric structural units of heparin (1-OMe ΔUA-2S, 1-OMe GlcN-S6S, 1,4-DiOMe GlcA, 1,4-DiOMe GlcN-S3S6S, 1,4-DiOMe IdoA-2S, and 1,4-DiOMe GlcN-S6S) have been studied in gas phase and aqueous solution as model reactions for formation of heparin-Ca2+ and heparin-Zn2+ complexes. Gibbs reaction energies computed at the B3LYP/6-311++G(d,p) level of theory for the reactions studied in aqueous solution are positive and range from 20 to 250 kJ/mol. © 2014 Elsevier B.V. All rights reserved.


Remko M.,Comenius University | Remko M.,Center for Hemostasis and Thrombosis | Herich P.,Slovak University of Technology in Bratislava | Gregan F.,Matej Bel University | Kozisek J.,Slovak University of Technology in Bratislava
Journal of Molecular Structure | Year: 2014

N-(4-Diethylaminoethoxybenzyl)benzene-1,4-bis(sulfonamide) (I-3) and its hydrochloride salt (I-3·HCl) were prepared. The X-ray molecular structure of (I-3·HCl) has been determined. The gas phase geometry of free base, its anion, cation and hydrochloride has been computed using Becke3LYP/6- 311++G(d,p) and B97D/6-311++G(d,p) model chemistry. The conformational behavior of these systems in water was examined using the solvation CPCM model. In the solid state this compound possesses a sandwich-like structure. According to the density functional calculations using B97D Grimme's functional including dispersion this structure is also present in the gas phase and/or in water solution. On the other hand, the B3LYP functional calculations prefer extended conformer in gas phase. The calculated gas-phase acidity and basicity are conformationally dependent and low, indicating that I-3 behaves as a weak acid and/or base.© 2013 Elsevier B.V.

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