Receptor-based virtual ligand screening for the identification of novel CDC25 phosphatase inhibitors

CDC25 phosphatases play critical roles in cell cycle regulation and are attractive targets for anticancer therapies. Several small non-peptide molecules are known to inhibit CDC25, but many of them appear to form a covalent bond with the enzyme or act through oxidation of the thiolate group of the catalytic cysteine. Structure-based virtual ligand screening computations were performed with FRED, Surflex, and LigandFit, a compound collection of over 310,000 druglike molecules and the crystal structure of CDC25B in order to identify novel classes of ligands. In vitro experiments carried out on a selected list of 1500 molecules led to the discovery of 99 compounds able to inhibit CDC25B activity at 100 microM. Further docking computations were applied, allowing us to propose a binding mode for the most potent molecule (IC50 = 13 microM). Our best compounds represent promising new classes of CDC25 inhibitors that also exhibit antiproliferative properties.     

Vector-valued lagrangian and multiobjective fractional programming duality

A class of multiobjective fractional programming problems is considered and duality results are established in terms of properly efficient solutions of the primal and dual programs. Further a vector-valued ratio type Lagrangian is introduced and certain vector saddlepoint results are presented.     

Some inequalities for fourier coefficients in inner product spaces

Some inequalities for Fourier coefficients in inner product spaces and related results are given. These inequalities complement, in a sense, some of the results in a recent book due to Mitrinovi, Peari and Fink.This research was supported by a grant from La Trobe University     

Complex Monodromy and Changing Real Pictures

The purpose of this note is to generalise, and give a more illuminatingproof, of a theorem of [13] (Theorem 1.1 below). Before statingit, we provide some introductory information. Consider the followingtwo sequences of pictures: in each we see a 1-parameter familyX_R,t of real algebraic hypersurfaces, which undergoes a bifurcationwhen the parameter t is equal to 0. Note that in Figure 1, both(i) (a) and (i) (b), and in (ii) (b), the surface X_R,t has apurely 1-dimensional part, which we have indicated with a dottedline, and that in (i) (b) we have drawn a curve vertically alongthe middle of the surface to make clearer the way it passesthrough itself. The reader will observe that in (a) the surfaceX_R,t is homotopically a 2-sphere when t>0 and a 0-spherewhen t<0, while in (b) X_R,t is a homotopy 1-sphere both fort<0 and t>0. Such sequences are typical in singularity theory; each is infact the family of algebraic closures of images of a versaldeformation of a codimension 1 singularity of mapping. Now suppose that the complexification X_C,t is a homotopy n-sphere.In [13] the second author pointed out that it follows that X_R,tis a homotopy sphere for t0 (allowing the empty set as a –1-sphere).Indeed, in the local situation, or globally in the weightedhomogeneous case, there are well-defined integers k₊ and k_–between –1 and n such that X_R,tS^k+ for t>0 and X_R,tS^k–for t<0. We describe X_R,t for tR–0 as ‘good’ if thehomotopy dimension of X_R,t is equal to n. In this case the inclusionX_R,tX_t is a homotopy equivalence [13, 1.1].     

Electronic Structure of the Ground and Excited States of β‐Carboline

Coupled‐cluster calculations are used to compute the energy of conversion between the neutral and the zwitterionic forms of β‐carboline. The stability of the different species is discussed in terms of charge separation and aromatic character, which is related to magnetic criteria. By means of a linear response formalism the vertical excitation energies and oscillator strengths of the lowest singlet states of both structures as well as of the cationic species are determined. General agreement of the relative position and intensity of the different peaks with experimental data is achieved, but the overall spectra are slightly displaced because of solvent effects.     

Spectroscopic, Phototropic, and Lasing Properties of Cd1−x Mn x Te Single Crystals Doped With Chromium Ions

The spectroscopic properties of Cr²⁺ ions in Cr:Cd_1–x Mn _x Te (CMT) crystals are studied, and the possibility of using these impurity crystals as active media and saturable absorbers of solidstate lasers of medium IR range is demonstrated. The bands of absorption with a maximum at 1.9 m and of luminescence with a maximum at 2.6 m correspond to the transitions between the levels ⁵ T ₂ and ⁵ E of the tetracoordinated Cr²⁺ ions with more than 1·10^–18cm² cross sections. The pulsed and continuous lasing modes of a Cr:CMT laser are realized in the 2.6m region. The Cr:CMT crystals are characterized by effective saturation of impurity absorption. The cross sections of absorption from the ground and excited states of the Cr²⁺ ions at = 2.09 m are determined: _gsa = 1.1·10^–18 cm²; _esa/_gsa < 0.1. With the use of the Cr:CMT crystals as a passive gate the regime of Qswitching of the Cr,Tm,Ho:YAG laser emitting at = 2.09 m is obtained.     

Efficient tunable laser operation of diode- pumped Yb,Tm:KY(WO4)2 around 1.9 μm

A new laser medium – Yb,Tm:KY(WO₄)₂ – for diode pumped solid state laser applications operating around 1.9 to 2.0 μm has been investigated and the main laser characteristics are presented. Diode pumping at 981 nm and around 805 nm was realised. For 981-nm pumping, the excitation occurs into Yb³⁺ ions followed by an energy transfer to Tm³⁺ions. A slope efficiency of 19% was realised. For pumping around 805 nm, the excitation occurs directly into the Tm³⁺ ions. Here a maximum slope efficiency of 52%, an optical efficiency of 40%, and output powers of more than 1 W were realised. Using a birefringent quartz plate as an intracavity tuning element, the tunability of the Yb,Tm:KY(WO₄)₂ laser in the spectral range of 1.85–2.0 μm has been demonstrated. The possibility of laser operation in a microchip cavity configuration for this material has also been shown. Received: 12 March 2002 / Revised version: 20 May 2002 / Published online: 25 September 2002 RID="*" ID="*"Corresponding author. Fax: +49-531/592-4116, E-mail: stefan.kueck@ptb.de