Biomedical subjects

V S Skvortsov

Publications and source records attributed to V S Skvortsov.

14 recordsLinked to original sources

PubMed2005

Quantifying hydrogen bonding in QSAR and molecular modeling.

Quantitative descriptions of hydrogen bonding for use in QSAR and molecular modeling by means of H-bond descriptors have been analyzed in detail in this paper. Ten new H-bond surface and enthalpy integral descriptors were proposed. The usefulness of these new descriptors, as well as previously developed descriptors was verified using a set of 154 drugs for which data for intestinal absorption in humans were available. The results showed that descriptors such as the number of H-bond acceptor and donor atoms and polar surface area (PSA) did not sufficiently describe the actual H-bonding ability of atoms in molecules. Thus, to enable successful modeling it was necessary to introduce descriptors directly related to the experimental thermodynamics of hydrogen bonding.

Humans↗

PubMed2004

[Structural-functional motifs of sterol 14-alpha demethylases (CYP51)].

CYP51 family of cytochromes P450 (sterol 14-alpha-demethylases) comprises the representatives from different kingdoms of living world, thus positioning itself as the most ancient member of the superfamily. In the course of the present research the collection of 36 full-length CYP51 amino acid sequences was submitted to cluster analysis. Each node of the clustering dendrogram corresponds to the groups of proteins, located on the branches descending from the node. By making the multiple alignment of each group of protein sequences we obtained the node-specific consensus sequences. The informational content of the consensus was defined as the presence of the compact conserved sites, the motifs. The assessment of informational content was computed using Sherman's non-parametric statistical criterion. The high informational content was observed for the 100% conserved consensus sequences of the following CYP51,s groups: fungi, animal+plant, plant+protista and bacteria. These selected consensus sequences were next aligned all together to get the final consensus for the whole family. To enrich the informational content of the CYP51 consensus the level of its conservation was dropped to 75%. Regions of statistically significant conservation were unraveled in the CYP51 consensus sequence. These regions (motifs) were then correlated with the information on secondary structure elements and substrate recognition sites reported for CYP51 from Mycobacterium tuberculosis. Seven motifs appeared to be obligatory for every CYP51 protein. The motifs thus obtained were searched for among all the known cytochrome P450 proteins. Some motifs were found to be absolutely specific for 14-alpha-demethylases, whereas others were common to different species of cytochromes P450.

Amino Acid Motifs↗

PubMed2001

An approach for visualization of the active site of enzymes with unknown three-dimensional structures.

A new approach for virtual characterization of the active site structure of enzymes with unknown three-dimensional (3D) structure has been proposed. It includes analysis of data on enzyme interaction with reversible competitive inhibitors, their 3D structures and moulding of the substrate-binding region. The superposition of ligands in biologically active conformations allows to determine the shape and dimension of the active site cavity accommodating these compounds. Monoamine oxidase A (MAO-A), a "typical" enzyme with unknown spatial organisation, was used to test this method. The correctness of such approach was validated by the analysis of HIV protease interaction with its inhibitors using 3D structures of their complexes. Mould of the substrate/inhibitor binding site can be used for the visualization of this binding site and for searching new ligands in molecular databases.

Databases, Factual↗

PubMed2000

Modeling of substrate-binding region of the active site of monoamine oxidase A.

The mold of the substrate-binding region of the active site of monoamine oxidase A (MAO A) was designed using data of the enzyme interaction with reversible competitive inhibitors and the analysis of their three-dimensional structures. The superposition of ligands in biologically active conformations allowed determination of the shape and dimension of the active site cavity accommodating these compounds. The correctness of this approach was validated by the analysis of HIV protease interaction with its inhibitors using three-dimensional structures of HIV protease-inhibitor complexes. The mold of the substrate/inhibitor-binding site can be used for searching for new ligands in molecular databases and the development of a new generation of MAO inhibitors using lead structures that have not been employed for this purpose yet.

Binding Sites↗

PubMed1995

[The rational computer-aided design of new drugs: a review of the methods].

Progress in computer science over recent 10 years has sharply reduced both the cost and the time spent on designing new drugs. Various concepts in solving this problem are now integrated into one approach--computer-assisted rational drug design. It consists of two groups of methods: 1) computer-assisted analysis of chemical structure-biological activity relationships by QSAR, OSMR, 3D QSAR and CoMFA; 2) computer modelling of the interaction of a ligand (a small drug molecule) with its target--a biological macromolecule, which is generally a protein. The findings of new ligands, which would selectively bind to the well-known protein can be done by screening the small molecules listed in some computer data bases. These new chemical structures can be used as a basis for drug designing.

Computer Simulation↗

PubMedDate not supplied

QSAR analysis of indole analogues as monoamine oxidase inhibitors.

The quantitative structure-activity relationship (QSAR) analysis with comparative molecular field analysis (CoMFA) of indole derivatives-monoamine oxidase (MAO) inhibitors were done. The pharmacophore model included four features: two hydrophobic rings, one donor atom, and one acceptor site. The predictive values (cross-validated r2) of QSAR analysis for the inhibition of MAO-A and MAO-B were 0.743 and 0.603, respectively. The contributions of steric and electrostatic fields in the interaction between inhibitors and enzymes were equal. The three-dimensional arrangement of these fields for MAO-A and MAO-B suggests that structures of active site for both enzymes are considerably differed from each other.

Binding Sites↗

PubMedDate not supplied

[Prediction of binding affinities of protein-ligand complexes using nonlinear models].

A network model for prediction of the free energy changes in protein-ligand complexes has been developed. The 150 complexes of different nature were used as a training set. The computational physics-chemical parameters of these complexes were used as independent variables. Both classical models of multiple linear regression and several network models with one hidden layer were created and the best was chosen. Significant improvement was shown for network model prediction quality in comparison with classical model of multiple linear regression (R2 on training--0.81 and 0.54; R2 on "leave-one-out" procedure--0.74 and 0.52 respectively).

Ligands↗

PubMedDate not supplied

[Computer modeling of the three-dimensional structure of full-length cytochrome B5].

The computer-aided reconstruction of 3D structure of full-length cytochrome b5 was done. Software Sybyl 6.4 from Tripos running on workstation Silicon Graphics Indigo2 (R4400, XZ) was used. The reconstruction was carried out by computer modelling of membrane part of cytochrom b5 with subsequent linking with known structure of water-soluble b5 part (fragment 5-91 of amino acid residues-file 3B5C in the protein data bank, PDB). The obtained structure of full-length cytochrome b5 was refined in the mixture of polar and nonpolar solvents by molecular dynamics simulation and deterministic minimization. Molecular dynamics simulation was performed in periodic box of binary system of solvents with a step of 1 fs during 550 ps at constant number of particles, pressure and temperature. The balance of system was achieved after 400 ps. With period in 5 ps the potential energy was minimized without molecular dynamics interruption. As a result 100 conformations of full-length cytochrome b5 were obtained. Distribution of potential energy was from -2.7 x 10(4) to -4.2 x 10(4) kcal/mol. Conformation of cytochrome b5 with minimal value of potential energy was accepted as the final. Analysis of lipophilic surface of obtained model have shown that membrane bounded part is more hydrophobic and forms a loop structure. This model corresponds to some known experimental data about cytochrome b5 structure.

Amino Acid Sequence↗

PubMedDate not supplied

[Computer drug design based on analysis of a target macromolecule structure. I. Search and description of a ligand binding site in a target molecule].

The applicability of molecular docking method for finding of ligand binding site in a target protein was tested. The basic principle of tested approach consists in generation of hypotheses of protein-ligand complexes by molecular docking of small ligand to all surface of protein. The subsequent scoring of these hypotheses utilizes the values of contact surfaces and complex formation energy. The docking procedure was executed using the original software DockSearch running on PC Pentium or SGI computers. A set of hypotheses of probable ligand positions on the protein surface was created and evaluated with the help of DockSearch. Energy minimization of molecular complexes was done using Sybyl 6.5 (Tripos Inc.) running on SGI server Origin 200. The final set of the best hypotheses of complexes were selected by the values of contact surfaces and complex formation energy. The applicability and the limits of this approach was tested using known 3D structures of different proteins in free state and in complexes with ligands. For most target proteins the method allows to find the ligand binding site correctly. The accuracy of description of ligand binding site is adequate for subsequent searching of lead compounds by database mining. The reasons of some negative results obtained in testing of this approach are also discussed.

Binding Sites↗

PubMedDate not supplied

[Computer model of 3D structure of cytochrome P450 2B4].

Cytochromes P450 (CYPs) play an important role in the oxidative metabolism of xenobiotics. Three-dimensional structures of CYPs are needed to study structure-function relationships in their molecules and interaction with partner proteins. Experimental determination of eucaryotic CYPs 3D structures is difficult because of hydrophobic membrane anchors and surface hydrophobic regions that prevent their crystallization. Replacement of surface hydrophobic amino acids by hydrophilic residues without any changes in protein structure and function can help to solve this problem. Such modification can be proposed using the analysis of 3D model of protein. In this work computer aided 3D structure of microsomal P450 2B4 (CYP2B4) was modeled for the further prediction of surface mutations for hydrophilization of the protein surface. The model of 3D structure of CYP2B4 was constructed by homology with CYP2C5 Model optimization was made by energy minimization and molecular dynamics simulation of protein molecule in water environment. The model was verified by using special statistic software and by comparison with the experimental data on the substrate recognition site, redox-partner binding sites and chemical modification of the protein surface.

Amino Acid Sequence↗

PubMedDate not supplied

[Computer modeling the cytochrome P450 three-dimensional structure: problems and prospects].

The review is devoted to the description of basic approaches, problems and prospects of computer modelling of 3D structures of cytochromes P450 (P450s). The following questions have been are considered in the review: (1) the role of computer molecular modelling in P450s research; (2) basic stages of homology modelling of protein 3D structures; (3) purposes and tasks of molecular modelling; (4) problems of P450s homology modelling; (5) criteria for successful P450s homology modelling; (6) methods of P450s models refinement, verification of correctness and reliability.

Amino Acid Sequence↗

PubMedDate not supplied

[Optical biosensor study and molecular modeling of interactions between cytochrome P450cam and cytochrome b5].

The formation of complexes of cytochrome P450cam (P450cam) with full-length cytochrome b5 (d-b5) and its tryptic water-soluble fragment (t-b5) was analyzed using a two-channel IAsys+ optical biosensor. It was found that t-b5 can form complexes with P450cam, while d-b5 does not interact with P450cam. The involvement of amine groups of P450cam in the complex formation was demonstrated. The temperature dependence of t-b5(im)/P450cam complex formation was measured. The association rate constant (k(on)) increased with temperature, while the dissociation rate constant (k(off)) practically remained unchanged. It was concluded that hydrophobic interactions play a key role in the complex formation, while electrostatic interactions are significant for complex stabilization. Based on temperature dependence the activation energy, enthalpy and entropy of complex formation were calculated. It was shown that the entropy component plays a key role in t-b5(im)/P450cam interaction. Computer modeling of P450cam/t-b5 and P450cam/d-b5 interactions was carried out. Using the method of molecular docking some hypotheses of protein-protein complexes were advanced and the best ones were selected based on geometric complementarity, calculated binding energy and probability of electron tunneling between proteins. The computer modeling has shown that only P450cam and t-b5 can form the stable complex. These results are in good agreement with the experimental data obtained with the optical biosensor.

Amino Acid Sequence↗

PubMedDate not supplied

[Balance of carbohydrate-containing biopolymers in the large intestine and mechanism of its impairments in ulcerous disease].

Excretion of carbohydrate-containing components of glycoproteins with feces was studied in patients with ulcerous disease, chronic gastritis, with cancer of stomach and in healthy persons. Content of glycoproteins, especially of fucoglycoproteins, was decreased in intestinal mucous during an acute period of the ulcerous disease. The same phenomenon was observed in epithelium of a distal part of small intestine. Remissions were accompanied by an increase in content of fucoglycoproteins in mucus and epithelium cells. These alterations in balance of glycoproteins were not found in other investigated impairments of the gastro-duodenal system.

Acute Disease↗

PubMedDate not supplied

[Modeling of a three-dimensional structure of cytochrome P-450 1A2 and search for its new ligands].

The substances inhibiting cytochrome P450 1A2 (CYP1A2) represent a perspective class of new drugs, which application in clinical practice can become the important part in preventive maintenance in oncology. The present work is devoted to computer modelling of 3-D structure of CYP1A2 and searching of new inhibitors by database mining. The modelling of CYP1A2 was done based on homology with 4 bacterial cytochromes P450 with known 3-D structure. For optimization of CYP1A2 active site structure the models of its complexes with characteristic substrates (caffeine and 7-ethoxyresorufin) were designed. These complexes were optimized by molecular dynamics simulation in water. The models of 24 complexes of CYP1A2 with known ligands with known Kd were designed by means of DockSearch and LeapFrog programs. 3D-QSAR model with good predictive force was created based on these complexes. On a final stage the search of knew CYP1A2 ligands in testing database (more than 23.000 substances from database Maybridge and 112 known CYP1A2 ligands from database Metabolite, MDL) was executed. 680 potential ligands of CYP1A2 with Kd values, comparable with known ones were obtained. This number has included 73 compounds from 112 known ligands, introduced in tested database as the internal control.

Amino Acid Sequence↗