The multiple roles of computational chemistry in fragment-based drug design

Fragment-based drug discovery (FBDD) represents a change in strategy from the screening of molecules with higher molecular weights and physical properties more akin to fully drug-like compounds, to the screening of smaller, less complex molecules. This is because it has been recognised that fragment hit molecules can be efficiently grown and optimised into leads, particularly after the binding mode to the target protein has been first determined by 3D structural elucidation, e.g. by NMR or X-ray crystallography. Several studies have shown that medicinal chemistry optimisation of an already drug-like hit or lead compound can result in a final compound with too high molecular weight and lipophilicity. The evolution of a lower molecular weight fragment hit therefore represents an attractive alternative approach to optimisation as it allows better control of compound properties. Computational chemistry can play an important role both prior to a fragment screen, in producing a target focussed fragment library, and post-screening in the evolution of a drug-like molecule from a fragment hit, both with and without the available fragment-target co-complex structure. We will review many of the current developments in the area and illustrate with some recent examples from successful FBDD discovery projects that we have conducted.     

Possibilities and limitations of synchrotron X-ray powder diffraction with double crystal and double multilayer monochromators for microscopic speciation studies

The performance of a combined microbeam X-ray fluorescence/X-ray powder diffraction (XRF/XRPD) measurement station at Hamburger Synchrotronstrahlungslabor (HASYLAB) Beamline L is discussed in comparison to that at European Synchrotron Radiation Facility (ESRF) ID18F/ID22. The angular resolution in the X-ray diffractograms is documented when different combinations of X-ray source, optics and X-ray diffraction detectors are employed. Typical angular resolution values in the range 0.3–0.5° are obtained at the bending magnet source when a ‘pink’ beam form of excitation is employed. A similar setup at European Synchrotron Radiation Facility beamlines ID18F and ID22 allows to reach angular resolution values of 0.1–0.15°. In order to document the possibilities and limitations for speciation of metals in environmental materials by means of Hamburger Synchrotronstrahlungslabor Beamline L X-ray fluorescence/X-ray powder diffraction setup, two case studies are discussed, one involved in the identification of the crystal phases in which heavy metals such as chromium, iron, barium and lead are present in polluted soils of an industrial site (Val Basento, Italy) and another involved in the speciation of uranium in depleted uranium particles (Ceja Mountains, Kosovo). In the former case, the angular resolution is sufficient to allow identification of most crystalline phases present while in the latter case, it is necessary to dispose of an angular resolution of ca. 0.2° to distinguish between different forms of oxidized uranium.     

Multiple time step update schemes for dissipative particle dynamics

In dynamical simulations of coarse-grained models of soft matter in a solvent a considerable amount of the total simulation time is generically spent on updating the solvent particles, although their dynamics is in most cases not of primary interest. In order to speed up such simulations and as a consequence allow to extend them to cover larger system sizes, we propose and examine various multiple, specifically dual, time step update algorithms for dissipative particle dynamics simulations that are based on the velocity-Verlet scheme [Phys. Rev. 159, 98 (1967)]. Common to all update variants is that the solvent beads are updated with a lower frequency than the bonded interactions within the solute. As a test case we consider a coarse-grained model of a lipid bilayer in water. Our results demonstrate that a considerable saving of simulation time can be gained, while the obtained simulation data are within error brackets virtually identical to those obtained for the reference single time step update scheme.     

Screening for galectin-3 inhibitors from synthetic lacto-N-biose libraries using microscale affinity chromatography coupled to mass spectrometry

The synthesis and screening of two beta-D-Galp-(1-3)-beta-d-GlcpN (lacto-N-biose) disaccharide libraries are reported. Solution-phase synthetic modifications at the HO-2' and NH positions were performed in an effort to enhance the affinity toward galectin-3, a galactose-binding protein involved in tumor metastasis, apoptosis, and inflammation. The libraries were screened for galectin-3 binding by microscale frontal affinity chromatography coupled to mass spectrometry (FAC/MS) allowing for rapid ranking of the different inhibitors and the determination of the galectin-3 binding Kd's. Compounds bearing a hydrophobic substituent on the NH group showed the highest affinity for the lectin. The N-naphthoyl derivative (Kd = 10.6 microM) was the best inhibitor with a 7 times increased affinity as compared to the N-acetyl parent compound (Kd = 73.3 microM).     

Tuning quadratic nonlinear photonic crystal fibers for zero group-velocity mismatch

We consider an index-guiding silica photonic crystal fiber with a triangular hole pattern and a periodically poled quadratic nonlinearity. By tuning the pitch and the relative hole size, second-harmonic generation with zero group-velocity mismatch is found for any fundamental wavelength above 780 nm. The nonlinear strength is optimized when the fundamental has maximum confinement in the core. The conversion bandwidth allows for femtosecond-pulse conversion, and 4%-180%W(-1)cm(-2) relative efficiencies were found.     

Coupling of discrete-element method and smoothed particle hydrodynamics for liquid-solid flows

Particle based methods can be used for both the simulations of solid and fluid phases in multiphase medium, such as the discrete-element method for solid phase and the smoothed particle hydrodynamics for fluid phase. This paper presents a computational method combining these two methods for solid-liquid medium. The two phases are coupled by using an improved model from a reported Lagrangian-Eulerian method. The technique is verified by simulating liquid-solid flows in a two-dimensional lid-driven cavity.     

Surface‐enhanced Raman microscopy of hemispherical shells stripped from templates of anodized aluminum

We report on the optical characterization of plasmonic metal nanostructures representing highly ordered interconnected hemispherical gold and silver shells that can be iteratively stripped from the same embossed templates (without template degradation) made from selectively etched anodized aluminum. By performing scanning high‐resolution confocal Raman microscopy of p‐aminothiophenol and Rhodamine 6G molecules homogeneously adsorbed to samples with different radii of shell curvature, we systematically investigate the applicability of the fabricated structures for surface‐enhanced Raman spectroscopy and correlate the results with linear reflection spectroscopy. We trace the origin of strong Raman signal enhancements (average relative enhancement of up to ~120) to electromagnetic hot‐spots located in sharp grooves and crevices at hemisphere shell junctions. Copyright © 2011 John Wiley & Sons, Ltd.     

Adaptive behaviour of the spinal cord in the transition from quiet stance to walking

Background

Parkinson??s disease is characterized by a continuous loss of neurons within the substantia nigra (SN) leading to a depletion of dopamine. Within the adult SN as a non-neurogenic region, cells with mainly oligodendrocytic precursor characteristics, expressing the neuro-glial antigen-2 (NG2) are continuously generated. Proliferation of these cells is altered in animal models of Parkinson??s disease (PD). Exercise and environmental enrichment re-increase proliferation of NG2⁺ cells in PD models, however, a possible mechanistic role of dopamine for this increase is not completely understood. NG2⁺ cells can differentiate into oligodendrocytes but also into microglia and neurons as observed in vitro suggesting a possible hint for endogenous regenerative capacity of the SN. We investigated the role of dopamine in NG2-generation and differentiation in the adult SN stimulated by physical activity and environmental enrichment.

Results

We used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-model for dopamine depletion and analysed newborn cells in the SN at different maturation stages and time points depending on voluntary physical activity, enriched environment and levodopa-treatment. We describe an activity- induced increase of new NG2-positive cells and also mature oligodendrocytes in the SN of healthy mice. Running and enriched environment refused to stimulate NG2-generation and oligodendrogenesis in MPTP-mice, an effect which could be reversed by pharmacological levodopa-induced rescue.

Conclusion

We suggest dopamine being a key regulator for activity-induced generation of NG2-cells and oliogodendrocytes in the SN as a potentially relevant mechanism in endogenous nigral cellular plasticity.     

High-performance slow light photonic crystal waveguides with topology optimized or circular-hole based material layouts

Photonic crystal waveguides are optimized for modal confinement and loss related to slow light with high group index. A detailed comparison between optimized circular-hole based waveguides and optimized waveguides with free topology is performed. Design robustness with respect to manufacturing imperfections is enforced by considering different design realizations generated from under-, standard- and over-etching processes in the optimization procedure. A constraint ensures a certain modal confinement, and loss related to slow light with high group index is indirectly treated by penalizing field energy located in air regions. It is demonstrated that slow light with a group index up to n_g = 278 can be achieved by topology optimized waveguides with promising modal confinement and restricted group-velocity-dispersion. All the topology optimized waveguides achieve a normalized group-index bandwidth of 0.48 or above. The comparisons between circular-hole based designs and topology optimized designs illustrate that the former can be efficient for dispersion engineering but that larger improvements are possible if irregular geometries are allowed.