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Milan  Remko
  • Bratislava, Slovakia

Milan Remko

The geometries of 19 biologically active substituted sulfonamides (including clinically useful acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, and brinzolamide) in both neutral and deprotonated forms, were... more
The geometries of 19 biologically active substituted sulfonamides (including clinically useful acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, and brinzolamide) in both neutral and deprotonated forms, were optimized using Becke3LYP/6-311+G(d,p) method (compounds 1-6) and two-layered ONIOM (B3LYP 6-311+G(d,p): MNDO) method (compounds 7-19). The investigated sulfonamides are weak acids with calculated acidity of about 1320-1420 kJ mol(-1). Of acids studied the highest gas-phase acidity (1324 kJ mol(-1)) possesses methazolamide. This drug is, according to the computed pKa value (5.9), also in water solution the most acidic compound of the sulfonamides investigated. The computed pKa values varied between 5.9 and 12.6 and correlate well with the available experimental pKa's found in the literature. Cancerostatic aromatic sulfonamides 16-19 are generally weak acids with the acidity comparable or slightly lower than the lead sulfanilamide. The available exp...
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select... more
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Ab initio molecular orbital methods are used to study local anesthetics of the ester, analide and carbamate types. Electrostatic molecular potential contour maps were evaluated for aromatic parts of those type of drugs. Because the main... more
Ab initio molecular orbital methods are used to study local anesthetics of the ester, analide and carbamate types. Electrostatic molecular potential contour maps were evaluated for aromatic parts of those type of drugs. Because the main constituents of cell membranes are lipids and proteins, our further SCF MO studies concerned interaction of polar groups of local anesthetics with possible associative sites of nerve membrane. Aniline, formanilide and trimethylamine represent possible associative sites of the local anesthetics procaine and lidocaine. Dimethylphosphate mono anion, o-phosphate monoanion, formate anion and acetamide represent the associate sites of the membrane. Finally, the binding of the amine group of drug with the Na+, K+, Ca2+ and Cl- ions present in vivo is also investigated.
The methods of theoretical chemistry have been used to elucidate the molecular properties of the substituted imidazoline and oxazoline structures, a class of potent agonists and antagonists of imidazoline receptors. The geometries of... more
The methods of theoretical chemistry have been used to elucidate the molecular properties of the substituted imidazoline and oxazoline structures, a class of potent agonists and antagonists of imidazoline receptors. The geometries of various tautomers and isomers of 2-[2,6-dichlorophenylimino]imidazolidine (clonidine), 1-(N-dicyclopropylmethyl)amino-2-oxazoline (rilmenidine), 4-chloro-N-(4,5-dihydro-1H-imidazol-2yl)-6-methoxy-2-methyl-5-pyrimidinamine (moxonidine), N-(dicyclopropylmethyl)-4,5-dihydro-1H-pyrrol-2-amine (aminopyrroline), N-dicyclopropylmethyl-4,5-dihydrothiazol-2-amine (aminothiazoline), 4,5-dihydro-2-(2-methoxyphenyl)-1H-imidazole (compound_6), 4,5-dihydro-2-(3-methylthiophen-2-yl)-1H-imidazole (compound_7), N-(2-chloro-4-iodophenyl)-4,5-dihydro-5-methyl-3H-pyrrol-2-amine (LNP_911), N-amidino-3,5-diamino-6-chloropyrazine-carboxamide (amiloride), 2-(1,4-benzodioxan-2-yl)-2-imidazoline (idazoxan), (+/-)-2-(2-ethyl-2,3-dihydro-2-benzofuranyl)-2-imidazoline (efaroxan), (...
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select... more
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
... MILAN REMKO" Department of Pharmaceutical Chemistry, Comenius University, Odbojarov 10, SK-832 32 Bratislava. ... Structure and general energetic considerations The enthalpies and Gibbs energies of the species studied are listed... more
... MILAN REMKO" Department of Pharmaceutical Chemistry, Comenius University, Odbojarov 10, SK-832 32 Bratislava. ... Structure and general energetic considerations The enthalpies and Gibbs energies of the species studied are listed in table 1. The fully optimized geome-tries ...
The methods of theoretical chemistry have been used to elucidate molecular properties of clinically useful acetazolamide, dorzolamide and brinzolamide and two new aromatic sulfonamides in both neutral and deprotonated forms. The... more
The methods of theoretical chemistry have been used to elucidate molecular properties of clinically useful acetazolamide, dorzolamide and brinzolamide and two new aromatic sulfonamides in both neutral and deprotonated forms. The geometries and energies of these drugs have been computed using HF/6–31G(d), Becke3LYP/6–31G(d) and Becke3LYP/6–311+G(d,p) model chemistries. The equilibrium structure of the acetazolamide is stabilized via intramolecular interaction between non-bonded S···O atoms of the acetylamino group and the thiadiazole ring. In the case of the aromatic sulfonamides (4-sulfamoyl-N-(3-morpholinopropyl) benzamide (P10), and N-(morpholinopropyl)benzene-1,4-bis(sulfonamide) (P20)) the fully optimized most stable conformers possess characteristic L-shape structure stabilized via intramolecular hydrogen bonding system of the N–H···N type. Computed partition coefficients (XLOGP2 method) for drugs studied varied between –0.3 and –1.8. Neutral compounds are described as slightly lipophilic drugs. The calculated water solubility of dorzolamide and brinzolamide is comparably low. P10 and P20 are slightly lipophilic sulfonamides with moderate solubility. The calculated pKa values of –SO2NH2 moiety in the sulfonamides studied are in the range of 7.3–9.7 and are characterized as weak organic acids.
Ab initio molecular orbital calculations at the CBS-Q level of theory have been used to study the rotational conformers and acidity of dithiosilanoic acid and several of its derivatives R-SiSSH (R=H, F, Cl, NH 2, OH and CH 3). For all six... more
Ab initio molecular orbital calculations at the CBS-Q level of theory have been used to study the rotational conformers and acidity of dithiosilanoic acid and several of its derivatives R-SiSSH (R=H, F, Cl, NH 2, OH and CH 3). For all six acids studied the syn conformers are predicted to have the lowest energy. The syn-anti enthalpy difference varies between 4 and 7 kJ mol -1. Dithiosilanoic acid is ˜60 and ˜96 kJ mol -1 more acid than dithioformic and silanoic acid, respectively.
Ab initio molecular orbital methods in combination with DFT calculations were used to study the structural and thermodynamic properties of 17 complexes containing zinc cation and four first-shell ligands as models of active site of... more
Ab initio molecular orbital methods in combination with DFT calculations were used to study the structural and thermodynamic properties of 17 complexes containing zinc cation and four first-shell ligands as models of active site of metalloenzymes (e.g. angiotensin converting enzyme, thermolysin). The geometry of the complexes was relaxed by complete optimization by ab initio molecular orbital methods at Hertree-Fock level with 3-21G* basis set. Following single point calculation with tight SCF criteria at the B3LYP level with 6-311+G(2d,p) basis set was used to calculate accurate interaction enthalpies. The structure and thermodynamics of optimized complexes are discussed from the point of view of their biological importance.
TheCNDO method in the modification ofDel Bene andJaffé was used for investigations on the electronic spectra of o-benzoquinone, 4-methyl-o-benzoquinone, hydroxy-p-benzoquinone and p-quinone methide.
Ab initio density functional theory calculations were used to investigate gas-phase acidities of three selected ACE inhibitors expressed as enthalpy of deprotonation at 298.15 K (ΔH298 K)- This study took advantage of the recently... more
Ab initio density functional theory calculations were used to investigate gas-phase acidities of three selected ACE inhibitors expressed as enthalpy of deprotonation at 298.15 K (ΔH298 K)- This study took advantage of the recently developed ONIOM method, which allowed to calculate properties of dissociating functional groups of ACE inhibitors with high accuracy with the Becke3LYP method with 6-311+G(d,p) basis set - the High layer, while the other atoms were included in the Low layer, for which the Hartree - Fock method with 3-21G* basis set was used. Structure and reactivity of captopril, perindoprilat, and omapatrilat and their respective ionic forms are discussed.
Ab initio molecular orbital methods at the CBS-QB3 level of theory have been used to study the structure and gas-phase stability of various tautomers and rotamers of N-hydroxyurea, N-hydroxythiourea, and N-hydroxysilaurea, their anions... more
Ab initio molecular orbital methods at the CBS-QB3 level of theory have been used to study the structure and gas-phase stability of various tautomers and rotamers of N-hydroxyurea, N-hydroxythiourea, and N-hydroxysilaurea, their anions and protonated forms. The geometries of N-hydroxyurea, N-hydroxythiourea, and N-hydroxysilaurea, their anions and cations were optimized at the Becke3LYP/CBSB7 level of theory. For all compounds studied, the
The effect of binding of cations (Na+, K+) on the geometry and strength of the complexes pairing protonated antiarrhythmics lidocaine NH+, tocainide NH+, and mexiletine NH+ with the anionic acetate group forming charged NH+⋯−O bonds was... more
The effect of binding of cations (Na+, K+) on the geometry and strength of the complexes pairing protonated antiarrhythmics lidocaine NH+, tocainide NH+, and mexiletine NH+ with the anionic acetate group forming charged NH+⋯−O bonds was studied using the ab initio SCF 3-21G level of theory. The coordination of the ions Na+ and K+ to the protonated antiarrhythmic–acetate systems considerably reduces the strength of the O−⋯+HN hydrogen bond. Of the two cations studied Na+ produces a larger destabilizing effect. The possible proton transfer from the drug towards the carboxylate anionic site was investigated in the case of the mexiletine NH+⋯−OCOCH3 complex. For both the isolated and the metal ion coordinated systems two-minima potentials at RO⋯N=2.75Å were found. The most stable minimum for the isolated system mexiletine NH+⋯−OCOCH3 corresponds to the neutral N⋯H–O hydrogen bond. In coordinated systems the presence of the cations Na+ and K+ in the vicinity of hydrogen bond considerably stabilize proton transfer structures. The most stable minimum in the coordinated systems correspond to charged O−⋯+HN complexes.
The crystal structures of captopril {systematic name: (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid}, C9H15NO3S, (1), and its dimer disulfide metabolite,... more
The crystal structures of captopril {systematic name: (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid}, C9H15NO3S, (1), and its dimer disulfide metabolite, 1,1'-{disulfanediylbis[(2S)-2-methyl-1-oxopropane-3,1-diyl]}bis-L-proline, C18H28N2O6S2, (2), were determined by single-crystal X-ray diffraction analysis. Compound (1) crystallizes in the orthorhombic space group P212121, while compound (2) crystallizes in the monoclinic space group P21, both with one molecule per asymmetric unit. The molecular geometries of (1) and (2) are quite similar, but certain differences appear in the conformations of the five-membered proline rings and the side chains containing the sulfhydryl group. The proline ring adopts an envelope conformation in (1), while in (2) it exists in envelope and slightly deformed half-chair conformations. The conformation adopted by the side chain is extended in (1) and folded in (2). A minimum-energy conformational search using Monte Carlo me...
ABSTRACT Our work reports in detail the results of systematic large-scale theoretical investigations of the complexes modeling heparin–protein interaction (CH3OSO3−Arg+, CH3NHSO3−Arg+, CH3CO2−Arg+, CH3OSO3−Lys+, CH3NHSO3−Lys+,... more
ABSTRACT Our work reports in detail the results of systematic large-scale theoretical investigations of the complexes modeling heparin–protein interaction (CH3OSO3−Arg+, CH3NHSO3−Arg+, CH3CO2−Arg+, CH3OSO3−Lys+, CH3NHSO3−Lys+, CH3CO2−Lys+, CH3OPO3H2−Arg+, CH3OPO3H2−Lys+, CH3O(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.
ABSTRACT 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... more
ABSTRACT 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 -16 000 kJ/ mol, which is the result of multiple coordinate bonds between ions and basic centers in glycosaminoglycan units.

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