Milan Remko

Acidity, lipophilicity, solubility, absorption, and polar surface area of some ACE inhibitors

Computational chemical methods have been used to correlate the molecular properties of the 10 ACE inhibitors (captopril, enalapril, perindopril, lisinopril, ramipril, trandolapril, quinapril, fosinopril, benazepril, and cilazapril) and some of their active metabolites (enalaprilat, perindoprilat, ramiprilat, trandolaprilat, quinaprilat, fosinoprilat, benazeprilat, and cilazaprilat). The computed pKa values correlate well with the available experimental values. In the dicarboxylic ACE inhibitors, the carboxyalkyl carboxylate group of the ACE inhibitors studied is more acidic than the C-terminal carboxylate. However, at physiological pH = 7.4 both carboxyl groups of ACE inhibitors are completely ionized and the dicarboxyl-containing ACE inhibitors behave as strong acids. The available experimental partition coefficients of these ACE inhibitors investigated are well reproduced by the neural network-based ALOGPs and the fragment-based KoWWiN methods. All parent drugs (and prodrugs), with the exception of fosinopril, are compounds with low lipophilicity. Calculated pKa, lipophilicity, solubility, absorption, and polar surface area of the most effective ACE inhibitors for the prevention of myocardial infarction, perindopril and ramipril, were found similar. Therefore, it is probable that the experimentally observed differences in the survival benefits in the first year after acute myocardial infarction in patients 65 years of age or older correlate closely to the physicochemical and pharmacokinetic characteristics of the specific ACE inhibitor that is used.

Thermodynamics of binding of Li+, Na+, Mg2+ and Zn2+ to Lewis bases in the gas phase

Abstract B3LYP/6-311+G(d,p) DFT method was used to characterize the 92 gas-phase complexes of 23 neutral and anionic ligands H 2 O, NH 3 , PH 3 , H 2 S, H 2 Si, HF, HCl, H 2 Ge, t -HSiOH, t -HGeOH, H 2 CO, NH 2 (H)CO, HCOOH, H 2 GeO, H 2 SiO, H 2 CNH, HCN, CO, OH − , SH − , SiH − and HCOO − with Li + , Na + , Mg 2+ and Zn 2+ . The basicity order of the ligands studied towards those cations exhibits a different ordering. There is no general correlation of basicities towards cations investigated. However, a very good correlation was found between the basicities towards monovalent cations Li + and Na + and between the basicities towards divalent cations Mg 2+ and Zn 2+ . Calculated values of interaction enthalpies and free energies vary as Zn 2+ >Mg 2+ ≫Li + >Na + . The relative basicities of the bases studied depend characteristically on type of cation and co-ordination base.

Bivalent cation binding effect on formation of the peptide bond

The reactions between formic acid (or glycine) and ammonia, without and with Mg2+, Ni2+ and Cu2+ cations as catalysts, have been studied as model reactions for peptide bond formation using the Becke3LYP functional and 6-311+G(d,p) basis set of DFT theory. Enthalpies and free energies for the stationary points of each reaction have been calculated to determine the thermodynamics of reactions investigated. A substantial decrease in reaction enthalpies and free energies was found for formic acid-ammonia and glycine-ammonia reactions catalysed by Mg2+, Ni2+ and Cu2+ ions compared with those of the uncatalysed amide bond formation. The catalytic effect of the transition metal ions Ni2+ and Cu2+ is of similar strength and more pronounced than that of the Mg2+ cation.

Effect of Metal Ions (Li+, Na+, K+, Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+) and Water Coordination on the Structure and Properties of L-Arginine and Zwitterionic L-Arginine

Interactions between metal ions and amino acids are common both in solution and in the gas phase. The effect of metal ions and water on the structure of L-arginine is examined. The effects of metal ions (Li(+), Na(+), K(+), Mg(2+), Ca(2+), Ni(2+), Cu(2+), and Zn(2+)) and water on structures of Arg x M(H2O)m , m = 0, 1 complexes have been determined theoretically by employing the density functional theories (DFT) and using extended basis sets. Of the three stable complexes investigated, the relative stability of the gas-phase complexes computed with DFT methods (with the exception of K(+) systems) suggests metallic complexes of the neutral L-arginine to be the most stable species. The calculations of monohydrated systems show that even one water molecule has a profound effect on the relative stability of individual complexes. Proton dissociation enthalpies and Gibbs energies of arginine in the presence of the metal cations Li(+), Na(+), K(+), Mg(2+), Ca(2+), Ni(2+), Cu(2+), and Zn(2+) were also computed. Its gas-phase acidity considerably increases upon chelation. Of the Lewis acids investigated, the strongest affinity to arginine is exhibited by the Cu(2+) cation. The computed Gibbs energies DeltaG(o) are negative, span a rather broad energy interval (from -150 to -1500 kJ/mol), and are appreciably lowered upon hydration.

Effect of metal Ions (Ni2+, Cu2+ and Zn2+) and water coordination on the structure of L-phenylalanine, L-tyrosine, L-tryptophan and their zwitterionic forms

Methods of quantum chemistry have been applied to double-charged complexes involving the transition metals Ni2+, Cu2+ and Zn2+ with the aromatic amino acids (AAA) phenylalanine, tyrosine and tryptophan. The effect of hydration on the relative stability and geometry of the individual species studied has been evaluated within the supermolecule approach. The interaction enthalpies, entropies and Gibbs energies of nine complexes Phe•M, Tyr•M, Trp•M, (M = Ni2+, Cu2+ and Zn2+) were determined at the Becke3LYP density functional level of theory. Of the transition metals studied the bivalent copper cation forms the strongest complexes with AAAs. For Ni2+and Cu2+ the most stable species are the NO coordinated cations in the AAA metal complexes, Zn2+cation prefers a binding to the aromatic part of the AAA (complex II). Some complexes energetically unfavored in the gas-phase are stabilized upon microsolvation.

Molecular structure, gas-phase acidity and basicity of N-hydroxyurea

The geometries of various tautomers and rotamers of N-hydroxyurea (aminoformohydroxamic acid), its anions and protonated forms were optimized at the Becke3LYP DFT level using the 6-311+G(d,p) basis set. The calculations showed that the molecule of neutral acid should exist in several forms very close in energy. The hydroxamic tautomer is about 42 kJ mol-1 more stable than the hydroximic structure. The most stable conformer of N-hydroxyurea is non-planar with the OH hydrogen atom out of the plane of heavy atoms. In the structure of the anion the intramolecular hydrogen bond stabilizes the structure and makes the most stable conformations more planar. The HON- anion is more stable than the O-anion, hence N-hydroxyurea in the gas phase is an N-acid. N-hydroxyurea is a weak acid with calculated acidity of about 1470 kJ mol-1. The hydroxyamide tautomer of N-hydroxyurea is an oxygen base in the gas phase. However, the effective polarization of the cations of extended planar hydroximic tautomers causes the unusual increase of the stability of N-cations. Hence the hydroximic tautomer should be protonated with almost the same probability. The proton affinity of N-hydroxyurea was computed to be -856.0 kJ mol-1.

Catalyzed Peptide Bond Formation in the Gas Phase. Role of Bivalent Cations and Water in Formation of 2-Aminoacetamide from Ammonia and Glycine and in Dimerization of Glycine

The formation of 2-aminoacetamide from ammonia and glycine and N-glycylglycine from two glycine molecules with and without Mg2+, Cu2+, and Zn2+ cations as catalysts have been studied as model reactions for peptide bond formation using the B3LYP functional with 6−311+G(d,p) and 6−31G(d) basis sets. The B3LYP method was also used to characterize the nine gas–phase complexes of neutral glycine, its amide (2-aminoacetamide), and N-glycylglycine with Lewis acids Mg2+, Cu2+, and Zn2+, respectively. Further, the gas-phase hydration of metal-coordinated complexes of glycine, 2-aminoacetamide, and N-glycylglycine was also investigated. Finally, the effect of water on the structure and reactivity of the metal coordinated complexes was determined. Enthalpies and Gibbs energies for the stationary points of each reaction have been calculated to determine the thermodynamics of the reactions investigated. A substantial decrease in reaction enthalpies and Gibbs energies was found for glycine–ammonia and glycine–glycine reactions coordinated by Mg2+, Cu2+, and Zn2+ ions compared to those of the uncoordinated 2-aminoacetamide bond formation. The formation of a dipeptide is a more exothermic process than the creation of simple 2-aminoacetamide from glycine. The energetic effect of the transition metal ions Cu2+ and Zn2+ is of similar strength and more pronounced than that of the Mg2+ cation. The basicity order of the amides investigated shows the order: NH2CH2CO2H < NH2CH2CONH2 < NH2CH2CONHCH2CO2H. Interaction enthalpies and Gibbs energies of metal ion–amide complexes increase as Mg2+<Zn2+<Cu2+. In both reactant (glycine) and reaction products (2-aminoacetamide, N-glycylglycine) dihydration caused considerable reduction (about 200–500 kJ-mol−1) of the strength of the bifurcated metal–amide bonds. Solvent effects also reduce the reaction enthalpy and Gibbs energy of reactions under study.

Catalyzed peptide bond formation in the gas phase

The reactions between glycine and ammonia and the dimerization of glycine with and without Mg2+, Ni2+, Cu2+ and Zn2+ cations as catalysts have been studied as model reactions for peptide bond formation using the Becke3LYP functional with 6-311 + G(d,p) and 6-31 + G(d) basis sets. The B3LYP method was also used to characterize the 12 gas-phase complexes of neutral glycine, its amide and glycylglycine with Lewis acids Mg2+, Ni2+, Cu2+ and Zn2+, respectively. Enthalpies and Gibbs energies for each reaction have been calculated to determine the thermodynamics of the reactions investigated. A substantial decrease in the reaction enthalpies and Gibbs energies was found for glycine–ammonia and glycine–glycine reactions catalyzed by Mg2+, Ni2+, Cu2+ and Zn2+ ions compared with those of the uncatalyzed amide bond formation. The formation of a dipeptide is a more exothermic process than the creation of simple amide from glycine. The catalytic effect of the transition metal ions Ni2+ Cu2+ and Zn2+ is of similar strength and more pronounced than that of the Mg2+ cation. The basicity order of the bases investigated is: NH2CH2CO2H<NH2CH2CONH2<NH2CH2CONHCH2CO2H. Interaction enthalpies and Gibbs energies of metal ion–base complexes increase as Mg2+<Zn2+<Cu2+<Ni2+.

Structure and gas phase stability of complexes L... M, where M = Li+, Na+, Mg2+ and L is formaldehyde, formic acid, formate anion, formamide and their sila derivatives

Ab initio SCF and DFT methods were used to characterize the gas-phase complexes of selected carbonyl and silacarbonyl bases with Li+, Na+ and Mg2+. Geometries were optimized at the Hartree-Fock ab initio and Becke 3LYP DFT levels with the 6-31G* basis set. Frequency computations were performed at the RHF/6-31G* level of theory. Interaction energies of the cation-coordinated systems also were determined with the MP2/6-31G* method. The effect of extension of basis set (to the 6-31+ G* basis) on the computed properties of anion-metal cation complexes was investigated. Calculated energies of formation vary as Mg2+ > Li++ > Na+. The Becke 3LYP DFT binding energies were comparable with those obtained at the correlated MP2 level and are in good agreement with available experimental data.

Theoretical study of molecular structure, tautomerism, and geometrical isomerism of N-methyl- and N-phenyl-substituted cyclic imidazolines, oxazolines, and thiazolines

The geometries of various tautomers and isomers of 2-methylamino-2-imidazoline, 2-methylamino-2-oxazoline, 2-methylamino-2-thiazoline, 2-phenylamino-2-imidazoline, 2-phenylamino-2-oxazoline, and 2-phenylamino-2-thiazoline have been studied using the Becke3LYP/6–31+G(d,p) DFT, ONIOM(Becke3LYP/6–31+G(d,p):HF/3–21G*) and ONIOM(Becke3LYP/6–31+G(d,p):AM1) methods. The optimized geometries indicate that these molecules show a distinctly nonplanar configuration of the cyclic moieties. In the gas phase, the amino tautomers (with exception of 2-phenylamino-2-imidazoline) are computed to be more stable than the imino tautomers. Of the two possible (E and Z) isomers of methyl and phenyl derivatives of imino-oxazolidine and imino-thiazolidine species, the (Z) isomers have the lowest energy. The iminozation free energies in the gas phase were found to be 5 – 15 kJ/mol. Absolute values of KT depend strongly on the accuracy of the method used for calculation of free energy. Solvation (using the MD simulations) causes, in most cases, a shift in tautomeric preference toward the imino species.