[Computer modeling the cytochrome P450 three-dimensional structure: problems and prospects]. / Komp'iuternoe modelirovanie prostranstvennoi struktury tsitokhromov P450: problemy i perspektivy.

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.

[Computer model of 3D structure of cytochrome P450 2B4]. / Komp'iuternaia model' trekhmernoi struktury tsitokhroma 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.

[Computer drug design based on analysis of a target macromolecule structure. I. Search and description of a ligand binding site in a target molecule]. / Komp'iuternoe konstruirovanie lekarstv na osnove analiza struktury makromolekuly-misheni: I. Poisk i opisanie mesta sviazyvaniia liganda v belke-misheni.

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.

[Computer searching of new targets for antimicrobial drugs based on comparative analysis of genomes]. / Komp'iuternyi poisk novykh mishenei dlia deistviia protivomikrobnykh sredstv na osnove sravnitel'nogo analiza genomov.

The progress in genome research allows to use genomic databases for drug discovery. The major interest consists in their usage for searching of new molecular targets for new drugs. It is especially important in the area of new antimicrobial drugs creation. In recent years, the applicability of genome analysis for solution of this problem was shown by different authors. We propose an approach for searching new targets for antimicrobial drugs based upon comparative analysis of genomes and samples from molecular databases. For each protein encoded by the target microorganism genome the conformance to a number of medico-biological and technological requirements was tested. The obtained evaluations were used for selection of potential targets. The approach was implemented in the original software GenMesh. It was successfully tested with known targets of drugs against tuberculosis when correct valuations were obtained. The attempt of new targets selection for design of new drugs against tuberculosis was done with reliable results.