Protonation states of molecules significantly influence the thermodynamics and kinetics of chemical reactions. This is especially important in biochemical processes, where appropriate protonation states of amino acids control the exo/endoergicity of practically all biochemical cycles. This paper is focused on appraisal of the impact of DFT functionals and PCM solvation models on the accuracy of pKa evaluations for all proteinogenic amino acids. Eight functionals (B3LYP, PBE0, revPBE0, M06-2X, M11, M11-L, TPSSh, and ωB97X-D) and four basis sets are considered, together with four kinds of implicit solvation models when additional attention is paid to a cavity construction. An influence of nonelectrostatic contributions and Wertz's corrections on Gibbs free energy is investigated together with accuracy of provided proton solvation energy. The best model is based on the M06-2X/6-311++G**/D-PCM/UAKS computational level. The fitting procedure is utilized to improve the accuracy of the evaluated models. All of these results are also compared with values obtained from the COSMOtherm program and CCSD(T) calculations. Results for cysteine and histidine are discussed individually, as they can be found in different protonation states at neutral pH.

• Publikační typ
• časopisecké články MeSH

Due to their high kinetic inertness and consequently reduced side reactions with biomolecules, PtIV complexes are considered to define the future of anticancer platinum drugs. The aqueous stability of a series of biscarboxylato PtIV complexes was studied under physiologically relevant conditions. Unexpectedly and in contrast to the current chemical understanding, especially oxaliplatin and satraplatin complexes underwent fast hydrolysis in equatorial position (even in cell culture medium and serum). Notably, the resulting hydrolysis products strongly differ in their reduction kinetics, a crucial parameter for the activation of PtIV drugs, which also changes the anticancer potential of the compounds in cell culture. The discovery that intact PtIV complexes can hydrolyze at equatorial position contradicts the dogma on the general kinetic inertness of PtIV compounds and needs to be considered in the screening and design for novel platinum-based anticancer drugs.

• Klíčová slova
• antitumor agents, hydrolysis, platinum(IV) complexes, prodrugs, reduction,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Interaction of cisplatin in activated diaqua-form with His-Met dipeptide is explored using DFT approach with PCM model. First the conformation space of the dipeptide is explored to find the most stable structure (labeled 0683). Several functionals with double-zeta basis set are used for optimization and obtained order of conformers is confirmed by the CCSD(T) single-point calculations. Supermolecular model is used to determine reaction coordinate for the replacement of aqua ligands consequently by N-site of histidine and S-site of methionine and reversely. Despite the monoadduct of Pt-S(Met) is thermodynamically less stable this reaction passes substantially faster (by several orders of magnitude) than coordination of cisplatin to histidine. The consequent chelate formation occurs relatively fast with energy release up to 12 kcal mol-1.

• Klíčová slova
• Anticancer drug, Computational chemistry, Density functional theory, Heavy metal, Thermodynamics,
• MeSH
• chelátory chemie   MeSH
• cisplatina chemie   MeSH
• dipeptidy chemie   MeSH
• histidin chemie   MeSH
• kinetika MeSH
• methionin chemie   MeSH
• protinádorové látky chemie   MeSH
• teorie funkcionálu hustoty * MeSH
• termodynamika MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory MeSH
• cisplatina MeSH
• dipeptidy MeSH
• histidin MeSH
• methionin MeSH
• protinádorové látky MeSH

Based on experimental work, 12 half-sandwich organoruthenium(II) complexes with p-cymene and various substituted β-diketonates (acac) modified by several functional groups were explored. These complexes were optimized at the B3PW91/6-31 + G(d)/PCM/UFF computational level with the Ru atom described by Stuttgart pseudopotentials. The electron density analysis was performed using the B3LYP/ 6-311++G(2df,2pd)/DPCM/scaled-UAKS model. Electrostatic and averaged local ionization potential were explored and extremes on 0.001 e/a.u.3 isodensity surfaces discussed. Natural population analysis partial charges and electron densities in bond critical point of the key Ru(II) coordination bonds were determined. There was a clear correlation between the results obtained and experimentally known anticancer descriptors. Graphical abstract Top Average local ionization potential (ALIP) of half-sandwich organoruthenium(II) β-diketonate complex, bottom IC 50 of b-series for ovarian cancer and Ru-P distances (in Å).

• Klíčová slova
• Anticancer Ru(II) complexes, DFT calculations, Half-sandwich complexes,
• Publikační typ
• časopisecké články MeSH

The thermodynamics of cisplatin and transplatin hydration is studied within the model of constant pH solution. Several implicit solvation models were chosen for the determination of pK(a) and pK constants of the hydration reactions. The polarizable dielectric model (DPCM), integral equation formalism polarizable model (IEFPCM), and polarizable conductor model (CPCM) were combined with the 'united atom model for Hartree-Fock' (UAHF) method for cavity construction and the B3LYP/6-31++G(2dp,2pd) level of calculations for the determination of electronic energies. The results were compared with the COSMO-RS and SM8 model developed by Truhlar (with M06 and MPWX functionals and the charge model CM4). The RMS difference between experimental and calculated pK(a) values of cis/transplatin, water, HCl, and NH (4) (+) was used to evaluate accuracy of calculations. The DPCM model was confirmed to perform the best. The predicted pK(a) constants were used in Legendre transformation for the estimation of the ΔG' energies in the constant-pH model. The dependence of the pK constant on pH is plotted and compared with experimental value at pH=7.4. The influence of various chloride concentrations on the molar fractions of dissolved forms of cisplatin is examined for the DPCM model. The increased ratio of cisplatin active aqua-forms is clearly visible for 4 mM chloride solution in comparison with 104 mM Cl(-) concentration.

• MeSH
• algoritmy MeSH
• chemické modely MeSH
• chloridy chemie   MeSH
• cisplatina chemie   MeSH
• hydrolýza MeSH
• komplexní sloučeniny chemie   MeSH
• koncentrace vodíkových iontů MeSH
• kvantová teorie MeSH
• počítačová simulace MeSH
• termodynamika * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chloridy MeSH
• cisplatina MeSH
• komplexní sloučeniny MeSH
• transplatin MeSH Prohlížeč