Biomedical subjects

Alexander V Veselovsky

Publications and source records attributed to Alexander V Veselovsky.

5 recordsLinked to original sources

PubMed2006

Epitope mapping of the domains of human angiotensin converting enzyme.

Somatic angiotensin converting enzyme (sACE), contains in its single chain two homologous domains (called N- and C-domains), each bearing a functional zinc-dependent active site. The present study aims to define the differences between two sACE domains and to localize experimentally revealed antigenic determinants (B-epitopes) in the recently determined three-dimensional structure of testicular tACE. The predicted linear antigenic determinants of human sACE were determined by peptide scanning ("PEPSCAN") approach. Essential difference was demonstrated between locations of the epitopes in the N- and C-domains. Comparison of arrangement of epitopes in the human domains with the corresponding sequences of some mammalian sACEs enabled to classify the revealed antigenic determinants as variable or conserved areas. The location of antigenic determinants with respect to various structural elements and to functionally important sites of the human sACE C-domain was estimated. The majority of antigenic sites of the C-domain were located at the irregular elements and at the boundaries of secondary structure elements. The data show structural differences between the sACE domains. The experimentally revealed antigenic determinants were in agreement with the recently determined crystal tACE structure. New potential applications are open to successfully produce mono-specific and group-specific antipeptide antibodies.

Amino Acid Sequence↗

PubMed2006

Bioinformatics platform development: from gene to lead compound.

In the past 10 yr, the field of bioinformatics has been characterized by the mapping of many genomes. These efforts have stimulated explosive development of novel bioinformatics and experimental approaches to predict the functions and metabolic role of the new proteins. The main application of the work is to search, validate, and prioritize new targets for designing a new generation of drugs. Modern computer and experimental methods for discovery of new lead compounds have also expanded and integrated into the process referred to as rational drug design. They are directed to accelerate and optimize the drug discovery process using experimental and virtual (computer-aided drug discovery) methods. Recently, these methods and approaches have merged into a "from gene to lead" platform that includes the processes from new target discovery through obtaining highly effective lead compounds. This chapter describes the strategies as employed by the "From Gene to Lead" platform, including the major computer and experimental approaches and their interrelationship. The latter part of the chapter contains some examples of the steps required for implementing this platform.

Computational Biology↗

PubMed2004

Computer modelling and visualization of active site of monoamine oxidases.

In spite of significant progress in MAO research culminating in the crystallization of the MAO B, many structure-functional aspects of these enzymes still require better characterization. Computer modelling of the substrate/inhibitory binding region of the active site includes consensus overlay of several series of fully reversible and/or tightly bound inhibitors onto a rigid referent inhibitor(s). The shape of resultant mould obviously reflects spatial characteristic features of the substrate/inhibitor binding region. The comparison of the active site mould of MAO B with its crystal structure revealed correctness of this approach. The resultant moulds may be effectively used for virtual screening of molecular databases for new lead-structures. Using this approach we have found several selective MAO A inhibitors in databases and these compounds have never been tested for MAO inhibitory activity.

Animals↗

PubMed2003

Protein-protein interactions as a target for drugs in proteomics.

Protein-protein interactions play a central role in numerous processes in the cell and are one of the main fields of functional proteomics. This review highlights the methods of bioinformatics and functional proteomics of protein-protein interaction investigation. The structures and properties of contact surfaces, forces involved in protein-protein interactions, kinetic and thermodynamic parameters of these reactions were considered. The properties of protein contact surfaces depend on their functions. The contact surfaces of permanent complexes resemble domain contacts or the protein core and it is reasonable to consider such complex formation as a continuation of protein folding. Characteristics of contact surfaces of temporary protein complexes share some similarities with active sites of enzymes. The contact surfaces of the temporary protein complexes have unique structure and properties and they are more conservative in comparison with active site of enzymes. So they represent prospective targets for a new generation of drugs. During the last decade, numerous investigations were undertaken to find or design small molecules that block protein dimerization or protein(peptide)-receptor interaction, or, on the contrary, to induce protein dimerization.

Computational Biology↗

PubMed2003

Computer visualisation of the active site of monoamine oxidase-A by means of selective inhibitors.

Computer visualisation of the active site of monoamine oxidase (MAO) is based on an assumption that the specific and reversible interaction of a ligand (substrate or inhibitor) with the substrate-binding region of the active site requires shape complementarity. The size of the ligand must allow its accommodation at the substrate-binding region. Analysis of the MAO-inhibitory activity of rigid analogues of isatin and pirlindole revealed a dependence between three-dimensional linear sizes of these molecules and the efficacy of inhibition of both MAO-A and MAO-B. However, flexible molecules did not exhibit any dependence between linear sizes and MAO-B inhibitory potency, possibly because they folded into compact structures could fit into the substrate-binding pocket of MAO-B. 'Moulding' of the substrate/inhibitor binding region by superposition of effective MAO-A inhibitors from various groups of chemicals allowed the shape of substrate/inhibitor binding region to be visualised. 'Removal of contents' from this mould yielded a cavity, which corresponded to the shape of substrate/inhibitor binding region. Such cavity can be used to evaluate the most probable positions known inhibitors take in binding to it. The docking procedure can also be used for searching molecular databases for new inhibitors. Pilot experiments revealed that relatively rigid compounds, which did not fit to this cavity, were poor inhibitors of MAO-A.

Journal Article↗