DENOPTIM: Software for Computational de Novo Design of Organic and Inorganic Molecules

A general-purpose software package, termed DE Novo OPTimization of In/organic Molecules (DENOPTIM), for de novo design and virtual screening of functional molecules is described. Molecules of any element and kind, including metastable species and transition states, are handled as chemical objects that go beyond valence-rules representations. Synthetic accessibility of the generated molecules is ensured via detailed control of the kinds of bonds that are allowed to form in the automated molecular building process. DENOPTIM contains a combinatorial explorer for screening and a genetic algorithm for global optimization of user-defined properties. Estimates of these properties may be obtained to form the fitness function (figure of merit or scoring function) from external molecular modeling programs via shell scripts. Examples of a range of different fitness functions and DENOPTIM applications, including an easy-to-do test case, are described. DENOPTIM is available as Open Source from https://github.com/denoptim-project/DENOPTIM.acceptedVersio

Automated in Silico Design of Homogeneous Catalysts

Catalyst discovery is increasingly relying on computational chemistry, and many of the computational tools are currently being automated. The state of this automation and the degree to which it may contribute to speeding up development of catalysts are the subject of this Perspective. We also consider the main challenges associated with automated catalyst design, in particular the generation of promising and chemically realistic candidates, the tradeoff between accuracy and cost in estimating the catalytic performance, the opportunities associated with automated generation and use of large amounts of data, and even how to define the objectives of catalyst design. Throughout the Perspective, we take a cross-disciplinary approach and evaluate the potential of methods and experiences from fields other than homogeneous catalysis. Finally, we provide an overview of software packages available for automated in silico design of homogeneous catalysts.publishedVersio

GAMMA: Eine Software für den automatischen Aufbau von Makromolekülen

Die Vielfalt möglicher makromolekularer Strukturen gepaart mit den explorativen Fähigkeiten computergestützter Generierung chemischer (Makro-)Molekülstrukturen bietet großes Forschungspotential. Die Eigenschaften solcher Strukturen, darunter häufig Hohlräume, in die kleine Moleküle passen, führen z. B. zu Anwendungen in Wirt-Gast-Strukturen. Das Hauptthema der vorliegenden Arbeit war die Entwicklung eines neuen Computerprogrammes, das, ausgehend von (kleinen) molekularen Bausteinen, makromolekulare Strukturen erstellt. Nach Vorgabe eines Templatgraphen werden molekulare Bausteine so miteinander verknüpft, dass ein Makromolekül entsteht. Dieses kann anschließend um polare funktionelle Gruppen erweitert werden, die das elektrische Feld des Makromoleküls gezielt verändern, um beispielsweise eine katalytische Wirkung zu entfalten

Building on Nature: Spectroscopic Studies of Photosynthesis-Inspired Pigments, Fused Light Harvesting Proteins, and Bacterial Reaction Center Mutants

Photosynthesis is the dominant form of solar energy conversion on the planet, making it critical to understand the fundamentals of the process in order to effectively mimic and improve upon it for human energy needs. The initial stages of photosynthesis include light harvesting and chemical conversion of that harvested energy via electron transport, with both of these stages relying on pigments (or chromophores) such as chlorophyll and specific protein architectures for the processes. In this work, the fundamental underpinnings of photosynthetic light harvesting and electron transport are explored via spectroscopy of various photosynthetic systems with altered natural pigments and proteins. Specifically, these include: 1) chlorophyll-like chromophores containing unnatural functional groups and their altered photophysical properties (such as red-shifted absorption), 2) purple bacterial reaction centers with modified native protein architecture and pigment content with increased \u27wrong-way\u27 electron transfer, and 3) purple bacteria wherein the non-photosynthetic pigment-protein complex yellow fluorescent protein (YFP) was added to the bacteriaճ natural reaction center, resulting in enhanced light-harvesting capacity

Synthesis and characterization of novel oxaliplatin analogs

In der vorliegenden Arbeit wurden unterschiedliche Derivate des Oxaliplatins entwickelt. Im ersten Projekt wurden sowohl das axiale, als auch das equatoriale Isomere des methylsubstituiertes Cyclohexandiaminligandens synthetisiert, und die entsprechenden Oxaliplatinanaloga hergestellt und mittels NMR, Elementaranalyse und Massenspektrometrie eindeutig charakterisiert. Das Isomer mit der axial orientierten Methylgruppe zeigte bessere Ergebnisse bezüglich der IC50 Werte. Der Effekt in der in vivo Untersuchung (Mausmodell, L1210) war jedoch entgegengesetzt, das equatorial substituierte Oxaliplatin zeigte eine bessere Aktivität. Im zweiten Projekt wurden zur Effizienzsteigerung des zellulären Transportes, neuartige Konjugate bestehend aus Oxaliplatin und dem TAT Peptid (Trans-Acting Activator of Transcription) synthetisiert. Das Peptid wurde durch Festphasensynthese hergestellt, wobei der Platinkomplex nach der letzten Aminosäure angefügt wurde. Die isolierten Mono- und Biskonjugate wurden mit NMR, ESI und MALDI MS bzw. Flüssigkeitschromatografie charakterisiert. Die beiden Substanzen zeigten eine bessere Zytotoxizität im Vergleich zum Ausgangskomplex bzw. zu einem Amidanalogon, das keine Gruppe im Sinne des Drug Targetings aufwies.In the first project the cyclohexanediamine ligands with axial and equatorial methyl group were synthesized and corresponding oxaliplatin derivatives were obtained. They were characterized with NMR, elemental analysis and mass spectrometry. In cytotoxicity tests, the one with axial orientation of the methyl group showed better results, the IC50 values were generally lower compared to oxaliplatin. The isomer with an equatorial orientation of the methyl group showed comparable or slightly higher values. In tests on leukemia mouse models better activity was shown by the equatorially substituted oxaliplatin. In the second project, conjugates of oxaliplatin featuring the TAT peptide (Trans-Acting Activator of Transcription) were prepared making the cellular transport more efficient. The peptide was synthesized on solid phase, the Pt complex was appended after the last amino acid. The obtained mono- and bisconjugates were characterized by NMR, ESI and MALDI MS and liquid chromatography. Both substances showed better cytotoxicity than the Pt precursor or the analogous amide without biologically relevant group

Paramagnetic chemical probes for studying biological macromolecules

Paramagnetic chemical probes have been used in electron paramagnetic resonance (EPR) and nuclear magnetic resonance (NMR) spectroscopy for more than four decades. Recent years witnessed a great increase in the variety of probes for the study of biological macromolecules (proteins, nucleic acids, and oligosaccharides). This Review aims to provide a comprehensive overview of the existing paramagnetic chemical probes, including chemical synthetic approaches, functional properties, and selected applications. Recent developments have seen, in particular, a rapid expansion of the range of lanthanoid probes with anisotropic magnetic susceptibilities for the generation of structural restraints based on residual dipolar couplings and pseudocontact shifts in solution and solid state NMR spectroscopy, mostly for protein studies. Also many new isotropic paramagnetic probes, suitable for NMR measurements of paramagnetic relaxation enhancements, as well as EPR spectroscopic studies (in particular double resonance techniques) have been developed and employed to investigate biological macromolecules. Notwithstanding the large number of reported probes, only few have found broad application and further development of probes for dedicated applications is foreseen.Macromolecular Biochemistr

The Generation of Novel Metal-Folate- Phenanthroline Complexes and Phenanthroline-Folate Conjugates with Potential as Chemotherapeutic Agents

The folate receptor (FR) was identified in 1986 and has been established as a ‘molecular Trojan Horse’ target for the uptake of folate-conjugated organic molecules into cells. The FR is overexpressed in many malignancies, including those of the ovary, uterus, breast, cervix, and prostate, yet it is reportedly under-expressed in normal healthy cells. This difference in expression and the high affinity/specificity of folate towards the folate receptor presents a promising drug delivery system. The aim of this research was to utilise folic acid as a targeting moiety and generate simple metal folate and novel folate-phenanthroline complexes with cytotoxic properties. A challenging set of chemical objectives were set and resulted in the successful generation of simple metal-folate and metal-folate-phen complexes (metal = Cu2+, Mn2+, Fe3+ and Zn2+). In contrast to reports in the literature, NMR and IR evidence indicates that the folate ligand coordinates the metal centre via a tridentate ONO {α-COO-, γ-COO-, and Namide} binding mode. A challenging six-stage synthetic route yielded the novel folate-ethylenediamine-imidazole-phen (FIMP-et) ligand and the novel complexes [Cu(FIMP-et)2(H2O)2].(ClO4)2.4.5H2O and [Mn(FIMP-et)3].(ClO4)2.9H2O were subsequently isolated in high yield and purity. The complexes generated were then utilised in a series of biological studies using cellular models expressing the folate receptor. Our results suggest that the effects mediated by these complexes are not dependent on folate receptor expression. Western blot analysis and live cell analysis identified that [Cu(fol)(phen)(H2O)].3H2O, with or without the inclusion of folic acid, induced expression of proteins associated with proteasomal inhibition and apoptosis. In contrast, [Mn(fol)(phen)(H2O)].4H2O was ineffective in inducing proteasomal inhibition. Interestingly [Mn(fol)(phen)(H2O)].4H2O induces cell death through a mechanism independent of proteasomal inhibition, which may involve ROS-induced autophagy. This work advances the field of medicinal inorganic chemistry and has identified novel mechanisms of action for metal folate targeted inorganic complexes as potential chemotherapeutic agents, through proteasomal inhibition and ROS-induced autophagy