We designed, synthesized, and evaluated novel 2,6,9-trisubstituted purine derivatives for their prospective role as antitumor compounds. Using simple and efficient methodologies, 31 compounds were obtained. We tested these compounds in vitro to draw conclusions about their cell toxicity on seven cancer cells lines and one non-neoplastic cell line. Structural requirements for antitumor activity on two different cancer cell lines were analyzed with SAR and 3D-QSAR. The 3D-QSAR models showed that steric properties could better explain the cytotoxicity of compounds than electronic properties (70% and 30% of contribution, respectively). From this analysis, we concluded that an arylpiperazinyl system connected at position 6 of the purine ring is beneficial for cytotoxic activity, while the use of bulky systems at position C-2 of the purine is not favorable. Compound 7h was found to be an effective potential agent when compared with a currently marketed drug, cisplatin, in four out of the seven cancer cell lines tested. Compound 7h showed the highest potency, unprecedented selectivity, and complied with all the Lipinski rules. Finally, it was demonstrated that 7h induced apoptosis and caused cell cycle arrest at the S-phase on HL-60 cells. Our study suggests that substitution in the purine core by arylpiperidine moiety is essential to obtain derivatives with potential anticancer activity.

• MeSH
• apoptóza účinky léků   MeSH
• kontrolní body fáze S buněčného cyklu účinky léků   MeSH
• krystalografie rentgenová MeSH
• kvantitativní vztahy mezi strukturou a aktivitou * MeSH
• lidé MeSH
• molekulární konformace MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Strukturní biologie se zabývá molekulární strukturou hlavně nukleových kyselin a proteinů a vlivu různých konformací na fyzikálně chemické vlastnosti. Rychlost a množství popsaných struktur je daleko za odhadovaným množstvím proteinů vyskytujících se v živých organismech a nové metody kombinují různé biofyzikální postupy... Příspěvek shrnuje nároky a výzvy různých metod strukturní biologie na IT infrastrukturu a možnosti souvisejícího výzkumu jako je fyziologie člověka a objevování léku. Na příkladu vlastní zkušenosti z projektu pro tzv. integrativní strukturní biologii, jsou vyčteny metody pro sdílení výpočetních metod, dat, autentizaci, autorizaci a podpory řízení procesu experimentu pro jeho účastníky.

• MeSH
• biologie buňky přístrojové vybavení   MeSH
• elektronová mikroskopie metody   přístrojové vybavení   MeSH
• krystalografie rentgenová metody   přístrojové vybavení   MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• nukleové kyseliny, nukleosidy a nukleotidy MeSH
• proteiny MeSH
• software MeSH
• ukládání a vyhledávání informací * metody   MeSH
• uživatelské rozhraní počítače MeSH
• vztahy mezi strukturou a aktivitou MeSH

Crystallography provides unique information about the arrangement of water molecules near protein surfaces. Using a nonredundant set of 2818 protein crystal structures with a resolution of better than 1.8 Å, the extent and structure of the hydration shell of all 20 standard amino-acid residues were analyzed as function of the residue conformation, secondary structure and solvent accessibility. The results show how hydration depends on the amino-acid conformation and the environment in which it occurs. After conformational clustering of individual residues, the density distribution of water molecules was compiled and the preferred hydration sites were determined as maxima in the pseudo-electron-density representation of water distributions. Many hydration sites interact with both main-chain and side-chain amino-acid atoms, and several occurrences of hydration sites with less canonical contacts, such as carbon-donor hydrogen bonds, OH-π interactions and off-plane interactions with aromatic heteroatoms, are also reported. Information about the location and relative importance of the empirically determined preferred hydration sites in proteins has applications in improving the current methods of hydration-site prediction in molecular replacement, ab initio protein structure prediction and the set-up of molecular-dynamics simulations.

• MeSH
• aminokyseliny analýza   MeSH
• databáze proteinů MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• proteiny chemie   MeSH
• sekundární struktura proteinů MeSH
• voda analýza   MeSH
• vodíková vazba MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

HIV protease (HIV PR) is a primary target for anti-HIV drug design. We have previously identified and characterized substituted metallacarboranes as a new class of HIV protease inhibitors. In a structure-guided drug design effort, we connected the two cobalt bis(dicarbollide) clusters with a linker to substituted ammonium group and obtained a set of compounds based on a lead formula [H(2)N-(8-(C(2)H(4)O)(2)-1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))-3,3'-Co)(2)]Na. We explored inhibition properties of these compounds with various substitutions, determined the HIV PR:inhibitor crystal structure, and computationally explored the conformational space of the linker. Our results prove the capacity of linker-substituted dual-cage cobalt bis(dicarbollides) as lead compounds for design of more potent inhibitors of HIV PR.

• MeSH
• elektrony MeSH
• HIV-1 enzymologie   účinky léků   MeSH
• HIV-proteasa chemie   metabolismus   MeSH
• inhibitory HIV-proteasy farmakologie   chemická syntéza   chemie   metabolismus   MeSH
• kobalt chemie   MeSH
• krystalografie rentgenová MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• racionální návrh léčiv MeSH
• sloučeniny boru chemická syntéza   chemie   farmakologie   metabolismus   MeSH
• uhlík chemie   MeSH
• Publikační typ
• práce podpořená grantem MeSH

Two structurally different copper(II) complexes of the compositions [{Cu(9dhx)(H2O)3}2(µ-SO4)2] (1) and [Cu(9dhx)2(H2O)2(NO3)2]·H2O (2), involving 9-deazahypoxanthine (9dhx; 6-oxo-9-deazapurine; 9-deazahypoxanthine), have been prepared and characterized by elemental analysis, infrared and electronic spectroscopy, electrospray ionisation (ESI) mass spectrometry, thermogravimetric (TG) and differential thermal (DTA) analyses, and cyclic voltammetry. The X-ray structures of complexes 1 and [Cu(9dhx)2(H2O)2(NO3)2] (2a) revealed the distorted octahedral geometry in the vicinity of the copper(II) atoms, with the NO5 and N2O4 donor set, respectively. In the dimeric compound 1, the {Cu(9dhx)(H2O)3}2 units are bridged by sulfate groups with the Cu···Cu separation being 5.3446(2) Å. In both structures the 9dhx ligands are coordinated through the N3 atoms of the pyrimidine moieties. The SOD-like activity of complexes 1 and 2 was evaluated in vitro showing moderate effect, with the IC50 values equal to 18.20, and 53.33 μM, respectively.

• MeSH
• biokompatibilní materiály chemie   metabolismus   MeSH
• elektrochemické techniky MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
• hypoxanthiny chemie   MeSH
• komplexní sloučeniny chemie   metabolismus   MeSH
• krystalografie rentgenová MeSH
• měď chemie   MeSH
• molekulární konformace MeSH
• spektroskopie infračervená s Fourierovou transformací MeSH
• superoxiddismutasa metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

3D macromolecular structural data is growing ever more complex and plentiful in the wake of substantive advances in experimental and computational structure determination methods including macromolecular crystallography, cryo-electron microscopy, and integrative methods. Efficient means of working with 3D macromolecular structural data for archiving, analyses, and visualization are central to facilitating interoperability and reusability in compliance with the FAIR Principles. We address two challenges posed by growth in data size and complexity. First, data size is reduced by bespoke compression techniques. Second, complexity is managed through improved software tooling and fully leveraging available data dictionary schemas. To this end, we introduce BinaryCIF, a serialization of Crystallographic Information File (CIF) format files that maintains full compatibility to related data schemas, such as PDBx/mmCIF, while reducing file sizes by more than a factor of two versus gzip compressed CIF files. Moreover, for the largest structures, BinaryCIF provides even better compression-factor ten and four versus CIF files and gzipped CIF files, respectively. Herein, we describe CIFTools, a set of libraries in Java and TypeScript for generic and typed handling of CIF and BinaryCIF files. Together, BinaryCIF and CIFTools enable lightweight, efficient, and extensible handling of 3D macromolecular structural data.

• MeSH
• chemické databáze MeSH
• komprese dat metody   MeSH
• krystalografie metody   MeSH
• makromolekulární látky chemie   ultrastruktura   MeSH
• molekulární modely * MeSH
• software * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

The adhesion of TiO(2) (anatase structure) nanoparticles to kaolinite substrate was investigated using molecular modeling. Universal force field computation, density function theory computation, and a combination of both two approaches were used. This study enabled the adhesion energy for the TiO(2)/kaolinite nanocomposite to be estimated, and revealed the preferred orientation of the TiO(2) nanoparticles on the kaolinite substrate. The results of all three levels of computation were compared in order to show that the accuracy of universal force field computations is sufficient in this context. The role of nanoparticle size and the importance of the nanoparticle-substrate bonding contribution are presented here and discussed. A comparison of the molecular modeling results with scanning electron microscopy observations showed that the results of the modeling were consistent with the experimental data, and that this approach can be used to help characterize nanocomposites of the nanoparticle/phyllosilicate substrate type.

• MeSH
• kaolin chemie   MeSH
• krystalografie MeSH
• kvantová teorie MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• nanočástice chemie   ultrastruktura   MeSH
• nanokompozity chemie   ultrastruktura   MeSH
• počítačová simulace MeSH
• povrchové vlastnosti MeSH
• termodynamika MeSH
• titan chemie   MeSH
• velikost částic MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH