Aggregation-based fluorescence amplification strategy: "turn-on" sensing of aminoglycosides using near-IR carbocyanine dyes and pre-micellar surfactants.

This study is aimed at developing sensing schemes without obtaining selective receptors. A series of simple carbocyanine dyes was synthesized, whose emission was quenched in water with formation of nanoparticles in the range of 20-100 nm. Fluorescence in near-IR region is "turned on" in the presence of a drug cation of middle molecular weight (400-700 Da) and sodium dodecyl sulfate (SDS), as well as anionic drugs and a cationic surfactant (cetyltrimethylammonium bromide, CTAB).

Non-covalent binding and selective fluorescent sensing of dipyrone with a carbocyanine dye and cetyltrimethylammonium bromide.

The work is aimed at the search of selective fluorescent sensors without using specific artificial receptors, antibodies, enzymes etc. With this end in view, methods based on non-covalent binding of target analytes are sought. We observed dramatic changes in the emission spectrum of a carbocyanine dye in a micellar surfactant solution (cetyltrimethylammonium bromide, CTAB) in the presence of dipyrone (metamizol, analgin): the 480 nm band intensity increases with a simultaneous decrease in intensity in near-IR region (720 nm).

New generation of docking programs: Supercomputer validation of force fields and quantum-chemical methods for docking.

Discovery of new inhibitors of the protein associated with a given disease is the initial and most important stage of the whole process of the rational development of new pharmaceutical substances. New inhibitors block the active site of the target protein and the disease is cured. Computer-aided molecular modeling can considerably increase effectiveness of new inhibitors development.

Evaluation of the novel algorithm of flexible ligand docking with moveable target-protein atoms.

We present the novel docking algorithm based on the Tensor Train decomposition and the TT-Cross global optimization. The algorithm is applied to the docking problem with flexible ligand and moveable protein atoms. The energy of the protein-ligand complex is calculated in the frame of the MMFF94 force field in vacuum.

Combined Docking with Classical Force Field and Quantum Chemical Semiempirical Method PM7.

Results of the combined use of the classical force field and the recent quantum chemical PM7 method for docking are presented. Initially the gridless docking of a flexible low molecular weight ligand into the rigid target protein is performed with the energy function calculated in the MMFF94 force field with implicit water solvent in the PCM model. Among several hundred thousand local minima, which are found in the docking procedure, about eight thousand lowest energy minima are chosen and then energies of these minima are recalculated with the recent quantum chemical semiempirical PM7 method.

Accuracy comparison of several common implicit solvent models and their implementations in the context of protein-ligand binding.

In this study several commonly used implicit solvent models are compared with respect to their accuracy of estimating solvation energies of small molecules and proteins, as well as desolvation penalty in protein-ligand binding. The test set consists of 19 small proteins, 104 small molecules, and 15 protein-ligand complexes. We compared predicted hydration energies of small molecules with their experimental values; the results of the solvation and desolvation energy calculations for small molecules, proteins and protein-ligand complexes in water were also compared with Thermodynamic Integration calculations based on TIP3P water model and Amber12 force field.

[Supercomputer investigation of the protein-ligand system low-energy minima].

The accuracy of the protein-ligand binding energy calculations and ligand positioning is strongly influenced by the choice of the docking target function. This work demonstrates the evaluation of the five different target functions used in docking: functions based on MMFF94 force field and functions based on PM7 quantum-chemical method accounting or without accounting the implicit solvent model (PCM, COSMO or SGB). For these purposes the ligand positions corresponding to the minima of the target function and the experimentally known ligand positions in the protein active site (crystal ligand positions) were compared.

Evaluation of Docking Target Functions by the Comprehensive Investigation of Protein-Ligand Energy Minima.

The adequate choice of the docking target function impacts the accuracy of the ligand positioning as well as the accuracy of the protein-ligand binding energy calculation. To evaluate a docking target function we compared positions of its minima with the experimentally known pose of the ligand in the protein active site. We evaluated five docking target functions based on either the MMFF94 force field or the PM7 quantum-chemical method with or without implicit solvent models: PCM, COSMO, and SGB.

Application of Molecular Modeling to Development of New Factor Xa Inhibitors.

In consequence of the key role of factor Xa in the clotting cascade and absence of its activity in the processes that do not affect coagulation, this protein is an attractive target for development of new blood coagulation inhibitors. Factor Xa is more effective and convenient target for creation of anticoagulants than thrombin, inhibition of which may cause some side effects. This study is aimed at finding new inhibitors of factor Xa by molecular computer modeling including docking SOL and postdocking optimization DISCORE programs.

Molecular modeling as a new approach to the development of urokinase inhibitors.

Proteolytic activity of urokinase plays an important role in negative remodeling of blood vessels, restenosis, tumor angiogenesis, and metastasizing, which necessitates the development of selective urokinase inhibitors. Using methods of computer modeling (docking, post processing, and direct docking) and quantum chemistry, we selected substances from the large compound database, analyzed their structures, and experimentally verified their inhibitor activity. New urokinase inhibitor candidates were proposed based on the theoretical predictions and experimental verification of compound activities.

Application of molecular modeling to urokinase inhibitors development.

Urokinase-type plasminogen activator (uPA) plays an important role in the regulation of diverse physiologic and pathologic processes. Experimental research has shown that elevated uPA expression is associated with cancer progression, metastasis, and shortened survival in patients, whereas suppression of proteolytic activity of uPA leads to evident decrease of metastasis. Therefore, uPA has been considered as a promising molecular target for development of anticancer drugs.

Application of the docking program SOL for CSAR benchmark.

This paper is devoted to results obtained by the docking program SOL and the post-processing program DISCORE at the CSAR benchmark. SOL and DISCORE programs are described. SOL is the original docking program developed on the basis of the genetic algorithm, MMFF94 force field, rigid protein, precalculated energy grid including desolvation in the frame of simplified GB model, vdW, and electrostatic interactions and taking into account the ligand internal strain energy.

[Ultrasound monitoring of the course of uveal melanoma].

Fifty-two persons were examined to define a role of a current ultrasound study during monitoring the natural history of uveal melanoma. The B-mode ultrasonography, color Doppler imaging and power Doppler and Doppler spectral study were applied. Ultrasound densitometry was used to estimate 326 sonograms imaging melanoma.

[Ultrasonography of intraocular pathology in a pediatric oncology clinic].

Forty-seven children with the intraocular acoustic effect of "plus-tissue", which was preconditioned by retinoblastoma, Coats' disease, retinopathy of the scarring stage in premature newborns and differentetiology fibroses of the vitreous body, underwent ultrasound examinations, including color Doppler mapping and pulse Doppler-graphy, for the purpose of promoting the differentiated diagnostics. Determinative ultrasonographic criteria were specified for each of the mentioned pathology states; a special significance of Doppler tools is pointed out in detecting a nature of the neovascular network, in identifying a.hyaloidea present in premature newborns and also present in retinal detachment with profound vitreous changes.

[Changes in the ocular and orbital blood flow in patients with retinal detachment treated surgically].

Sixty-eight patients with dystrophic regmatogenic detachment of the retina and 78 controls with different clinical refraction were examined by triplex scanning of the eyeball. Bloodflow parameters in the orbital artery, central retinal artery, posterior short ciliary arteries were evaluated before and in various periods after the operation. Characteristics of the bloodflow in the ocular and orbital arteries in myopia, detachment of the retina in the presence of myopic and emmetropic refraction, proliferative vitreoretinopathy of various degrees and patterns of its progress during the postoperative period were determined and time course of bloodflow parameters evaluated in some types of interventions.

[Vascular network of choroid melanoma as shown by triple ultrasonic examination].

Twenty-four patients (24 eyes) with choroid melanoma were examined by triplex ultrasonic examination (gray-scale scanning in the real time mode, color Doppler mapping, and pulse wave dopplerography). All tumors possessed individual vascular network with larger vessels with higher bloodflow velocity at the periphery in comparison with the center of the tumor. A large feeding vessel growing into the tumor at the periphery along the internal (facing the vitreous body) surface of the tumor was detected in the overwhelming majority of cases.

[Quantitative evaluation of ultrasonic images in differential diagnosis of bulky intraocular formations].

A method for evaluating ultrasonic gray-scale images by plotting amplitude histograms is proposed. From amplitude histogram analysis, echogenicity and homogeneity indexes of the examined tissues were estimated. A total of 213 images of bulky intraocular formations in 58 patients were analyzed by this method.

[Functional and morphological characteristics of the stress-protective effect of piracetam].

The functional and morphological manifestations of the protective effect of piracetam were studied on the model of two-day stress. Piracetam was shown to preserve the central nervous system functional activity, to decrease the pathophysiological and morphological manifestations of the stress syndrome.