Biomedical subjects

Vladimir V Poroikov

Publications and source records attributed to Vladimir V Poroikov.

6 recordsLinked to original sources

PubMed2006

Rational design of macrolides by virtual screening of combinatorial libraries generated through in silico manipulation of polyketide synthases.

Bacterial secondary metabolites display diverse biological activities, thus having potential as pharmacological agents. Although most of these compounds are discovered by random screening, it is possible to predict and re-design their structures based on the information on their biosynthetic pathways. Biosynthesis of macrolides, governed by modular polyketide synthases (PKS), obeys certain rules, which can be simulated in silico. PKS mode of action theoretically allows for a huge number of macrolides to be produced upon combinatorial manipulation. Since engineering of all possible PKS variants is practically unfeasible, we created Biogenerator software, which simulates manipulation of PKS and generates virtual libraries of macrolides. These libraries can be screened by computer-aided prediction of biological activities, as exemplified by analysis of erythromycin and macrolactin libraries. This approach allows rational selection of macrolides with desired biological activities and provides instructions regarding the composition of the PKS gene clusters necessary for microbial production of such molecules.

Combinatorial Chemistry Techniques↗

PubMed2005

Computer-aided rodent carcinogenicity prediction.

The potential of the computer program PASS (Prediction Activity Spectra for Substances) to predict rodent carcinogenicity for chemical compounds was studied. PASS predicts carcinogenicity of chemical compounds on the basis of their structural formula and of structure-activity relationship analysis of known carcinogens and non-carcinogens. The data on structures and experimental results of 2-year carcinogenicity assays for 412 chemicals from the NTP (National Toxicological Program) and 1190 chemicals from the CPDB (Carcinogenic Potency Database) were used in our study. The predictions take into consideration information about species and sex of animals. For evaluation of the predictive accuracy we used two procedures: leave-one-out cross-validation (LOO CV) and leave-20%-out cross-validation. In the last case we randomly divided the studied data set 20 times into two subsets. The data from the first subset, containing 80% of the compounds, were added to the PASS training set (which includes about 46,000 compounds with about 1500 biological activity types collected during the last 20 years to predict biological activity spectra), the second subset with 20% of the compounds was used as an evaluation set. The mean accuracy of prediction calculated by LOO CV is about 73% for NTP compounds in the 'equivocal' category of carcinogenic activity and 80% for NTP compounds in the 'evidence' category of carcinogenicity. The mean accuracy of prediction for the CPDB database is 89.9% calculated by LOO CV and 63.4% calculated by leave-20%-out cross-validation. Influence of incorporation of species and sex data on the accuracy of carcinogenicity prediction was also investigated. It was shown that the accuracy was increased only for data on male animals.

Animals↗

PubMed2005

Novel antitumor agents: marine sponge alkaloids, their synthetic analogs and derivatives.

Present review describes research on novel natural antitumor agents isolated from marine sponges. More than 90 novel cytotoxic antitumor compounds and their synthetic analogs have shown confirmed activity in vitro tumor cell lines bioassay and are of current interest to NCI for further in vivo evaluation. A great problem, to use directly the reservoir of marine organisms for therapy is the very low availability and the isolation of only very small amounts of the biologically active substances from the natural materials. Thus, the synthetic chemistry is required to develop high yield synthetic methods, which are able to produce sufficient marine alkaloids for a broad biological screening. This review will present some of the aspects of the medicinal chemistry developed recently to introduce such modifications. The structures, origins, synthesis and biological activity of a selection of N-heterocyclic marine sponge alkaloids are reviewed. The emphasis is on compounds poised as potential anticancer drugs: pyrroles, pyrazines, imidazole, and other structural families. With computer program PASS some additional biological activities are also predicted, which point toward new possible applications of these compounds. This review emphasizes the role of marine sponge alkaloids as an important source of leads for drug discovery.

Alkaloids↗

PubMed2004

Design of new cognition enhancers: from computer prediction to synthesis and biological evaluation.

To discover new cognition enhancers, a set of virtually designed synthesizable compounds from different chemical series was investigated using two computer-aided approaches. One of the approaches is prediction of biological activity spectra for substances (PASS) and the second is prediction of toxicity, mutagenicity, and carcinogenicity (DEREK). To increase the probability of finding new chemical entities, we investigated a heterogeneous set of highly diverse chemicals including different types of heterocycles: five-membered (thiophenes, thiazoles, imidazoles, oxazoles, pyrroles), six-membered (pyridines, pyrimidines), seven-membered (diazepines, triazepines), fused five+six-membered heterocycles (indoles, benzothiazoles, purines, indolizines, neutral, mesoionic, and cationic azolopyridines). A database including 5494 structures of compounds was created. On the basis of the PASS and DEREK prediction results, eight compounds with the highest probability of cognition-enhancing effect were selected. The cognition-enhancing activity testing showed that all of the selected compounds had a pronounced antiamnesic effect and were found to reduce significantly scopolamine-induced amnesia of passive avoidance reflex (PAR). The action of compounds at doses of 1 and 10 mg/kg caused a statistically significant increase in latent time of reflex and in the number of animals, which did not enter the dark chamber when testing the PAR. Therefore, on the basis of computer prediction, new cognition-enhancing agents were discovered within the chemical series, in which this activity was not known previously.

Amnesia↗

PubMed2003

Computer-aided selection of potential antihypertensive compounds with dual mechanism of action.

The prediction of biological activity spectra for substances as an approach for searching compounds with complex mechanisms of action was studied. New compounds with dual mechanisms of antihypertensive action were found by this approach. Biological activity spectra for substances were predicted on the basis of their structural formulas by the computer program PASS. Thirty molecular mechanisms of action of compounds from the MDDR 99.2 database, which cause the antihypertensive effect and can be predicted by PASS, have been identified. The analysis of predictions for compounds with 15 dual antihypertensive mechanisms of action from the MDDR 99.2 database has confirmed high accuracy of prediction. This approach was applied to databases of commercially available compounds (AsInEx and ChemBridge) and allowed us to select four substances that are potential inhibitors of angiotensin converting enzyme (ACE) and of neutral endopeptidase (NEP). At a later time, all these compounds were found to be the inhibitors of both ACE and NEP. The most potent compounds had IC(50) of 10(-7)-10(-9) M for ACE and 10(-5) M for NEP. New combinations of dual mechanisms of action never before found for antihypertensive compounds were predicted.

Angiotensin-Converting Enzyme Inhibitors↗

PubMedDate not supplied

PASS biological activity spectrum predictions in the enhanced open NCI database browser.

The application of the program PASS (Prediction of Activity Spectra for Substances) to about 250 000 compounds of the NCI Open Database and the incorporation of over 64 million PASS predictions in the Enhanced NCI Database Browser are described. A total of 565 different types of activity are included, encompassing general pharmacological effects, specific mechanisms of action, known toxicities, and others. Application of this Web-based service to prediction of activities of the kinds "Angiogenesis inhibitor," "Antiviral (HIV)", and a set of activities that can be associated with antineoplastic action are reported. For this latter data set, a very substantial enrichment over random selection was found in the PASS predictions. It is shown how the user can conduct complex searches by combining ranges of PASS-predicted probabilities of compounds to be active or to be inactive, respectively, with, e.g., value ranges of physicochemical parameters, presence or absence of particular substructural fragment, and other search criteria.

Antineoplastic Agents↗