Virtual fragment screening: an exploration of various docking and scoring protocols for fragments using Glide

Fragment-based drug discovery approaches allow for a greater coverage of chemical space and generally produce high efficiency ligands. As such, virtual and experimental fragment screening are increasingly being coupled in an effort to identify new leads for specific therapeutic targets. Fragment docking is employed to create target-focussed subset of compounds for testing along side generic fragment libraries. The utility of the program Glide with various scoring schemes for fragment docking is discussed. Fragment docking results for two test cases, prostaglandin D2 synthase and DNA ligase, are presented and compared to experimental screening data. Self-docking, cross-docking, and enrichment studies are performed. For the enrichment runs, experimental data exists indicating that the docking decoys in fact do not inhibit the corresponding enzyme being examined. Results indicate that even for difficult test cases fragment docking can yield enrichments significantly better than random. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Methyl-Induced Polarization Destabilizes the Noncovalent Interactions of N-Methylated Lysines

Lysine methylation can modify noncovalent interactions by altering lysine's hydrophobicity as well as its electronic structure. Although the ramifications of the former are documented, the effects of the latter remain largely unknown. Understanding the electronic structure is important for determining how biological methylation modulates protein−protein binding, and the impact of artificial methylation experiments in which methylated lysines are used as spectroscopic probes and protein crystallization facilitators. The benchmarked first-principles calculations undertaken here reveal that methyl-induced polarization weakens the electrostatic attraction of amines with protein functional groups – salt bridges, hydrogen bonds and cation-π interactions weaken by as much as 10.3, 7.9 and 3.5 kT, respectively. Multipole analysis shows that weakened electrostatics is due to the altered inductive effects, which overcome increased attraction from methyl-enhanced polarizability and dispersion. Due to their fundamental nature, these effects are expected to be present in many cases. A survey of methylated lysines in protein structures reveals several cases in which methyl-induced polarization is the primary driver of altered noncovalent interactions; in these cases, destabilizations are found to be in the 0.6–4.7 kT range. The clearest case of where methyl-induced polarization plays a dominant role in regulating biological function is that of the PHD1-PHD2 domain, which recognizes lysine-methylated states on histones. These results broaden our understanding of how methylation modulates noncovalent interactions.     

Blue emission from cysteine ester passivated cadmium sulfide nanoclusters

A one-pot synthesis is reported of water-soluble cadmium sulfide nanoclusters capped with cysteine ester, with an average size of 2.0 nm and fluorescing in the blue region, establishing the possibility of using these as fluorescent biological probes.     

Spin and pseudospin symmetric Dirac particles in the field of Tietz-Hua potential including Coulomb tensor interaction＊

Approximate analytical solutions of the Dirac equation for Tietz-Hua (TH) potential including Coulomb-like tensor (CLT) potential with arbitrary spin-orbit quantum number κ are obtained within the Pekeris approximation scheme to deal with the spin-orbit coupling terms κ(κ± 1)r-2 . Under the exact spin and pseudospin symmetric limitation, bound state energy eigenvalues and associated unnormalized two-component wave functions of the Dirac particle in the field of both attractive and repulsive TH potential with tensor potential are found using the parametric Nikiforov-Uvarov (NU) method. The cases of the Morse oscillator with tensor potential, the generalized Morse oscillator with tensor potential, and the non-relativistic limits have been investigated.     

Design and analysis of MEMS MWCNT/epoxy strain sensor using COMSOL

Wiesenfeld and Faure investigated rotational quenching of H ₂CO by molecular hydrogen where they considered 40 rotational levels of o-H ₂CO and 41 rotational levels of p-H ₂CO. Data on energies of rotational levels of the molecule are fundamental in the investigation. We have found that the sequence of levels reported by Wiesenfeld and Faure is not as per convention of molecular physics. Their results are also available on the website: http://www.home.strw.leidenuniv.nl/~moldata/datafiles/ph2co-h2.dat, where the collisional transitions are shown even between the levels having equal energies. Data for such transitions should not be there.     

XPS characterization of the surface immobilization of antibacterial furanones

Brominated furanones have attracted recent interest as antibacterial compounds. To utilize them as protective coatings in biomedical device applications, they must be covalently immobilized onto solid surfaces; however, interfacial coupling protocols developed for other biomolecules are not applicable to furanones. An azide reaction scheme has enabled covalent immobilization onto fluorinated ethylene propylene copolymer but its chemistry is less predictable, requiring detailed characterization by XPS and tapping mode AFM after each step of the immobilization sequence. XPS curve fitting resolved components in the C 1s, N 1s and Br 3d regions. Angle dependent XPS was used to assess the depth distributions and layer thicknesses. The results indicated successful covalent immobilization of furanones; however, side reactions occurred. In addition to the expected CBr, a contribution from bromine ion (Br⁻) was detected, indicating that photo-degradation of furanones took place during UV illumination, and this reaction was found to increase with illumination time. The Br⁻ was removed by washing with water, whereas the CBr signal from immobilized furanone remained. Spectroscopic characterization will assist in elucidating the structure of furanone coatings, understanding their mode of action when covalently immobilized on surfaces, and rationally designing and optimizing an effective antibacterial coating for biomedical applications.     

Solutions of the spatially-dependent mass Dirac equation with the spin and pseudospin symmetry for the Coulomb-like potential

We study the effect of spatially-dependent mass function over the solution of the Dirac equation with the Coulomb potential in the (3+1)-dimensions for any arbitrary spin-orbit κ state. In the framework of the spin and pseudospin symmetry concept, the analytic bound state energy eigenvalues and the corresponding upper and lower two-component spinors of the two Dirac particles are obtained by means of the Nikiforov-Uvarov method, in closed form. This physical choice of the mass function leads to an exact analytical solution for the pseudospin part of the Dirac equation. The special cases , the constant mass and the non-relativistic limits are briefly investigated.     

Dynamic Evolution of an Evaporating Liquid Meniscus from Structured Screen Meshes

Evaporation from screen mesh is a fundamental phenomenon that plays a vital role in thermal transport devices like heat pipes. Here, a laser scanning confocal microscopy setup has been utilized to study the effect of screen mesh wettability and its surface morphology on the evolution of evaporating liquid menisci from its liquid saturated pores. Stainless steel screen meshes (mesh #100 and #200) that are inherently hydrophobic in nature are turned super-hydrophilic by controlled heat treatment. The heat treatment leads to growth of oxide layer on the wire mesh and a change in surface morphology via formation of microscale pores, which improves the wettability of the screen mesh. The evaporation of liquid meniscus from pores of these untreated and heat-treated meshes is captured through confocal microscopy, and the dynamic evolution of the radius of curvature of the liquid meniscus is evaluated. A simple geometrical model is developed to predict the minimum radius of curvature \((R_{\mathrm{min}})\) of liquid meniscus in mesh pores just before its rupture (pore dryout). Meshes with high wettability, and smaller pore spacing-to-wire diameter ratio, are found to encounter a smaller \(R_{\mathrm{min}}\) before meniscus rupture. In addition, the water pore saturation inventory of the screen meshes are also measured to evaluate the effect of wettability on their water-holding capacity of screen meshes. Increase in screen mesh wettability is found to increase its pore saturation inventory. This increase in mesh pore saturation inventory coupled with the lower \(R_{\mathrm{min}}\) for super-hydrophilic mesh delays the liquid meniscus rupture (mesh dryout), leading to a much longer evaporation timescale for high wettability screen meshes.     

A novel pyrrole synthesis

The silver(I)-promoted oxidative cyclization of homopropargylamines at room temperature provides a novel access to pyrroles. Homopropargylamines are readily available by the addition of a propargyl Grignard reagent to Schiff bases.