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Alexis S Ivanov

Publications and source records attributed to Alexis S Ivanov.

2 recordsLinked to original sources

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↗

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↗