Virtual and experimental high-throughput screening (HTS) in search of novel inosine 5′-monophosphate dehydrogenase II (IMPDH II) inhibitors

IMPDH (Inosine 5??-monophosphate dehydrogenase) catalyzes a rate-limiting step in the de novo biosynthesis of guanine nucleotides. IMPDH inhibition in sensitive cell types (e.g., lymphocytes) blocks proliferation (by blocking RNA and DNA synthesis as a result of decreased cellular levels of guanine nucleotides). This makes it an interesting target for cancer and autoimmune disorders. Currently available IMPDH inhibitors such as mycophenolic acid (MPA, uncompetitive inhibitor) and nucleoside analogs (e.g., ribavirin, competitive inhibitor after intracellular activation by phosphorylation) have unfavorable tolerability profiles which limit their use. Hence, the quest for novel IMPDH inhibitors continues. In the present study, a ligand-based virtual screening using IMPDH inhibitor pharmacophore models was performed on in-house compound collection. A total of 50,000 virtual hits were selected for primary screen using in vitro IMPDH II inhibition up to 10???M. The list of 2,500 hits (with >70?% inhibition) was further subjected to hit confirmation for the determination of IC₅₀ values. The hits obtained were further clustered using maximum common substructure based formalism resulting in 90 classes and 7 singletons. A thorough inspection of these yielded 7 interesting classes in terms of mini-SAR with IC₅₀ values ranging from 0.163???M to little over 25???M. The average ligand efficiency was found to be 0.3 for the best class. The classes thus discovered represent structurally novel chemotypes which can be taken up for further development.     

Semi-Synthesis and Analysis of Chemically Modified Zif268 Zinc-Finger Domains

Total synthesis of proteins can be challenging despite assembling techniques, such as native chemical ligation (NCL) and expressed protein ligation (EPL). Especially, the combination of recombinant protein expression and chemically addressable solid-phase peptide synthesis (SPPS) is well suited for the redesign of native protein structures. Incorporation of analytical probes and artificial amino acids into full-length natural protein domains, such as the sequence-specific DNA binding zinc-finger motifs, are of interest combining selective DNA recognition and artificial function. The semi-synthesis of the natural 90 amino acid long sequence of the zinc-finger domain of Zif268 is described including various chemically modified constructs. Our approach offers the possibility to exchange any amino acid within the third zinc finger. The realized modifications of the natural sequence include point mutations, attachment of a fluorophore, and the exchange of amino acids at different positions in the zinc finger by artificial amino acids to create additional metal binding sites. The individual constructs were analyzed by circular dichroism (CD) spectroscopy with respect to the integrity of the zinc-finger fold and DNA binding.     

Antidiarrhetic loperamide hydrochloride

Single crystals of the anhydrous form of the title compound {systematic name: 1‐[3‐(dimethylcarbamoyl)‐3,3‐diphenylpropyl]‐4‐hydroxy‐4‐(4‐chlorophenyl)piperidin‐1‐ium chloride}, C₂₉H₃₄ClN₂O₂⁺·Cl⁻, were obtained by diffusion of acetone into a solution in 2‐propanol. In the structure, N—H...Cl⁻ and O—H...Cl⁻ hydrogen bonds connect neighbouring molecules and chloride anions to form chains along the c‐axis direction. Neighbouring chains along the b‐axis direction are connected by intermolecular C—H...Cl⁻ contacts, defining layers parallel to the (100) planes. The layers are connected by weak intermolecular C—H...Cl interactions only, which may account for the plate‐like shape of the crystals.     

Analysis of the influence of polymer viscosity on the dispersion of magnesium hydroxide in a polyolefin matrix

The dispersion of Mg(OH)₂ agglomerates at low concentration in a polymer melt was investigated in a transparent counter-rotating shear cell. The influence of the viscosity of the matrix, the initial agglomerate size and the infiltration of the matrix was evaluated. Mg(OH)₂ agglomerates have a low cohesion and a fractal structure. Two dispersive mechanisms already mentioned in the literature were identified: erosion and rupture. Critical conditions for rupture were measured and particle size analysis was performed in order to determine the kinetics of erosion. The infiltration of the matrix, which depends on the viscosity, was found to play a key role on dispersion mechanisms. In contrast to previous works, infiltration is more important with the high viscosity matrix. In infiltrated matrix, rupture was found to occur firstly through plastic deformation of the infiltrated agglomerate, and then the agglomerates split into small fragments. In the low viscosity matrix, fragments produced either by rupture or erosion are small aggregates.     

Magnetic properties of two double‐layer structures built from hydroxy­naphthoic acids and manganese

Double‐layer structures consisting of alternating polar and non‐polar layers have been prepared using Mn²⁺ ions and o‐hydroxy­naphthoic acids. The polar layers contain the Mn²⁺ ions, carboxylate groups, hydr­oxy groups and water mol­ecules. The non‐polar layers are built up from the naphthalene moieties. In catena‐poly[[diaqua­manganese(II)]bis­(μ‐3‐hy­droxy‐2‐naphthoato‐κ²O:O′)] (also called manganese 3‐hy­droxy‐2‐naphthoate dihydrate), [Mn(C₁₁H₇O₃)₂(H₂O)₂]_n, (I), the Mn²⁺ ions are connected by carboxylate groups to form two‐dimensional networks. This compound shows distinct antiferromagnetic inter­actions and long‐range ordering at low temperature. In contrast, tetra­aqua­bis(1‐hydr­oxy‐2‐naph­thoato‐κO)manganese(II), [Mn(C₁₁H₇O₃)₂(H₂O)₄], (II), which lacks a close linkage between the Mn²⁺ ions, reveals purely paramagnetic behaviour. In (II), the Mn²⁺ ion lies on an inversion centre.     

Auslander–Buchweitz Approximation Theory for Triangulated Categories

We introduce and develop an analogous of the Auslander–Buchweitz approximation theory (see Auslander and Buchweitz, Societe Mathematique de France 38:5–37, 1989) in the context of triangulated categories, by using a version of relative homology in this setting. We also prove several results concerning relative homological algebra in a triangulated category $\mathcal{T},$ which are based on the behavior of certain subcategories under finiteness of resolutions and vanishing of Hom-spaces. For example: we establish the existence of preenvelopes (and precovers) in certain triangulated subcategories of $\mathcal{T}.$ The results resemble various constructions and results of Auslander and Buchweitz, and are concentrated in exploring the structure of a triangulated category $\mathcal{T}$ equipped with a pair $(\mathcal{X},\omega),$ where $\mathcal{X}$ is closed under extensions and ω is a weak-cogenerator in $\mathcal{X},$ usually under additional conditions. This reduces, among other things, to the existence of distinguished triangles enjoying special properties, and the behavior of (suitably defined) (co)resolutions, projective or injective dimension of objects of $\mathcal{T}$ and the formation of orthogonal subcategories. Finally, some relationships with the Rouquier’s dimension in triangulated categories is discussed.     

Mean relaxation time approximation for dynamical correlation functions in stochastic systems near instabilities

The linewidth factor of the order parameter autocorrelation function for the mean fieldn-vector Ginzburg-Landau model is determined numerically forn>2. This generalizes results for the single mode laser (n=2) obtained in Part II [Nadler, W., Schulten, K.: Z. Phys. B—Condensed Matter].     

From molecular to macroscopic engineering: shaping hydrogen-bonded organic nanomaterials

The self‐assembly and self‐organization behavior of chromophoric acetylenic scaffolds bearing 2,6‐bis(acetylamino)pyridine ( 1 , 2 ) or uracyl‐type ( 3 – 9 ) terminal groups has been investigated by photophysical and microscopic methods. Systematic absorption and luminescence studies show that 1 and 2 , thanks to a combination of solvophilic/solvophobic forces and π–π stacking interactions, undergo self‐organization in apolar solvents (i.e., cyclohexane) and form spherical nanoparticles, as evidenced by wide‐field optical microscopy, TEM, and AFM analysis. For the longer molecular module, 2 , a more uniform size distribution is found (80–200 nm) compared to 1 (20–1000 nm). Temperature scans in the range 283–353 K show that the self‐organized nanoparticles are reversibly formed and destroyed, being stable at lower temperatures. Molecular modules 1 and 2 were then thoroughly mixed with the complementary triply hydrogen‐bonding units 3 – 9 . Depending on the specific geometrical structure of 3 – 9 , different nanostructures are evidenced by microscopic investigations. Combination of modules 1 or 2 with 3 , which bears only one terminal uracyl unit, leads to the formation of vesicular structures; instead, when 1 is combined with bis‐uracyl derivative 4 or 5 , a structural evolution from nanoparticles to nanowires is observed. The length of the wires obtained by mixing 1 and 4 or 1 and 5 can be controlled by addition of 3 , which prompts transformation of the wires into shorter rods. The replacement of linear system 5 with the related angular modules 6 and 7 enables formation of helical nanostructures, unambiguously evidenced by AFM. Finally, thermally induced self‐assembly was studied in parallel with modules 8 and 9 , in which the uracyl recognition sites are protected with tert‐butyloxycarbonyl (BOC) groups. This strategy allows further control of the self‐assembly/self‐organization process by temperature, since the BOC group is completely removed on heating. Microscopy studies show that the BOC‐protected ditopic modules 8 self‐assemble and self‐organize with 1 into ordered linear nanostructures, whereas BOC‐protected tritopic system 9 gives rise to extended domains of circular nano‐objects in combination with 1 .     

Estimating Second-Order Characteristics of Inhomogeneous Spatio-Temporal Point Processes

Non-parametric estimates of the K-function and the pair correlation function play a fundamental role for exploratory and explanatory analysis of spatial and spatio-temporal point patterns. These estimates usually require information from outside of the study region, resulting to the so-called edge effects which have to be corrected. They also depend on first-order characteristics, which have to be estimated in practice. In this paper, we extend classical edge correction methods to the spatio-temporal setting and compare the performance of the related estimators for stationary/non-stationary and/or isotropic/anisotropic point patterns. Further, we explore the influence of the estimated intensity function on these estimators.     

Universal models via embedding and reduction for locally conformal symplectic structures

We obtain universal models for several types of locally conformal symplectic manifolds via pullback or reduction. The relation with recent embedding results for locally conformal Kähler manifolds is discussed.