Tatyana A. Gloriozova

Chemical Similarity Assessment through Multilevel Neighborhoods of Atoms: Definition and Comparison with the Other Descriptors

A new method for assessment of molecular similarity based on original description of chemical structure is discussed. The accuracy of similarity assessment obtained with this method is compared with that of the results of four other approaches. The same evaluation set is used to predict:  (a) boiling point of 139 hydrocarbons and (b) mutagenicity of 15 nitrosamines. The results show that the proposed method provides reasonable appraisal for both properties, but prediction of mutagenicity is more accurate in this method as compared to the alternatives.

Collaborative development of predictive toxicology applications

OpenTox provides an interoperable, standards-based Framework for the support of predictive toxicology data management, algorithms, modelling, validation and reporting. It is relevant to satisfying the chemical safety assessment requirements of the REACH legislation as it supports access to experimental data, (Quantitative) Structure-Activity Relationship models, and toxicological information through an integrating platform that adheres to regulatory requirements and OECD validation principles. Initial research defined the essential components of the Framework including the approach to data access, schema and management, use of controlled vocabularies and ontologies, architecture, web service and communications protocols, and selection and integration of algorithms for predictive modelling. OpenTox provides end-user oriented tools to non-computational specialists, risk assessors, and toxicological experts in addition to Application Programming Interfaces (APIs) for developers of new applications. OpenTox actively supports public standards for data representation, interfaces, vocabularies and ontologies, Open Source approaches to core platform components, and community-based collaboration approaches, so as to progress system interoperability goals.The OpenTox Framework includes APIs and services for compounds, datasets, features, algorithms, models, ontologies, tasks, validation, and reporting which may be combined into multiple applications satisfying a variety of different user needs. OpenTox applications are based on a set of distributed, interoperable OpenTox API-compliant REST web services. The OpenTox approach to ontology allows for efficient mapping of complementary data coming from different datasets into a unifying structure having a shared terminology and representation.Two initial OpenTox applications are presented as an illustration of the potential impact of OpenTox for high-quality and consistent structure-activity relationship modelling of REACH-relevant endpoints: ToxPredict which predicts and reports on toxicities for endpoints for an input chemical structure, and ToxCreate which builds and validates a predictive toxicity model based on an input toxicology dataset. Because of the extensible nature of the standardised Framework design, barriers of interoperability between applications and content are removed, as the user may combine data, models and validation from multiple sources in a dependable and time-effective way.

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.

Natural Peroxy Anticancer Agents

Present review describes research on novel natural anticancer agents isolated from terrestrial and marine sources. More than 120 cytotoxic anticancer compounds have shown confirmed activity in vitro tumor cell lines bioassay and are of current interest to Natural Cancer Institute for further in vivo evaluation. Intensive searches for new classes of pharmacologically potent agents produced by terrestrial and marine organisms have resulted in the discovery of dozens of compounds possessing high cytotoxic activities. However, only a limited number of them have been tested in pre-clinical and clinical trials. One of the reasons is a limited supply of the active ingredients from the natural sources. However, the pre-clinical and clinical development of many terrestrial and/or marine-derived natural products into pharmaceuticals is often hampered by a limited supply from the natural source. Total synthesis is of vital importance in these situations, allowing for the production of useful quantities of the target compound for further biological evaluation. 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 terrestrial and marine peroxides as an important source of leads for drug discovery.

CLC-Pred: A freely available web-service for in silico prediction of human cell line cytotoxicity for drug-like compounds

In silico methods of phenotypic screening are necessary to reduce the time and cost of the experimental in vivo screening of anticancer agents through dozens of millions of natural and synthetic chemical compounds. We used the previously developed PASS (Prediction of Activity Spectra for Substances) algorithm to create and validate the classification SAR models for predicting the cytotoxicity of chemicals against different types of human cell lines using ChEMBL experimental data. A training set from 59,882 structures of compounds was created based on the experimental data (IG50, IC50, and % inhibition values) from ChEMBL. The average accuracy of prediction (AUC) calculated by leave-one-out and a 20-fold cross-validation procedure during the training was 0.930 and 0.927 for 278 cancer cell lines, respectively, and 0.948 and 0.947 for cytotoxicity prediction for 27 normal cell lines, respectively. Using the given SAR models, we developed a freely available web-service for cell-line cytotoxicity profile prediction (CLC-Pred: Cell-Line Cytotoxicity Predictor) based on the following structural formula: http://way2drug.com/Cell-line/.

Pharmacological and Predicted Activities of Natural Azo Compounds

This paper describes research on natural azo compounds isolated from fungi, plant, bacteria, and invertebrates. More than 120 biologically active diazene containing alkaloids demonstrate confirmed pharmacological activity, including antitumor, antimicrobial, and antibacterial effects. The structures, origin, and biological activities of azo compounds are reviewed. Utilizing the computer program PASS, some structure–activity relationship new activities are also predicted, pointing toward possible new applications of these compounds. This article emphasizes the role of natural azo compounds as an important source of drug prototypes and leads for drug discovery.

Highly oxygenated isoprenoid lipids derived from fungi and fungal endophytes: Origin and biological activities

HIGHLIGHTSMini review is devoted to highly oxygenated isoprenoid lipids that are produced by fungi and fungal endophytes.Fungal endophytes were obtained from brown and red algae, marine invertebrates and/or from marine sediments.Highly oxygenated isoprenoid lipids have the pharmacological potential on anti‐hypercholesterolemic, anti‐neoplastic, anti‐eczematic and anti‐inflammatory activity estimated with a confidence of 84–90%. ABSTRACT This mini review is devoted to highly oxygenated isoprenoid lipids (HOIL) that are produced by fungi and fungal endophytes from various ecological niches, both terrestrial and aquatic. Steroids were distributed as from edible cultivated fungi, as well as fungi collected in forests. Fungal endophytes were generally isolated from plants and cultured to obtain sufficient biomass. Marine fungi were obtained from marine brown and red algae and marine invertebrates such as sponges, corals, worms, crustacea or from marine sediments. HOIL isolated from the terrestrial ecosystem have the pharmacological potential on anti‐hypercholesterolemic, anti‐neoplastic, anti‐eczematic and anti‐inflammatory activity estimated with a confidence of 84–90%. HOIL that produced by marine fungal species are predicted as having anti‐inflammatory and anti‐hypercholesterolemic activity with a confidence of 82–91%. In addition, they may have potential acetylcholinesterase and cell adhesion molecule inhibitors estimated with a confidence of 86–88%.

Naturally occurring aromatic steroids and their biological activities

The present review describes the distribution and biological activities of natural mono-, di-, and triaromatic steroids. It is shown that the producers of aromatic steroids are microorganisms, fungi, and marine invertebrates, and also they were found in plants, animals, marine sediments, and karst deposits. Eighty biologically active aromatic steroids likely have an anti-tumor, anti-inflammatory, and neuroprotection activity with a confidence of 78 to 92%. The structures and predicted biological activities of aromatic steroids are available. This review emphasizes the role of aromatic steroids as an important source and potential leads for drug discovery and they are of great interest to chemists, physicians, biologists, pharmacologists, and the pharmaceutical industry.

Steroid phosphate esters and phosphonosteroids and their biological activities

Steroid phosphate esters are very rare natural lipids that have been comparatively recently isolated from fractions of polar lipids of marine sponges and starfish. These steroids exhibit interesting biological activities. When using the PASS computer program, we showed that many of steroid phosphate esters showed antifungal, antihypercholesterolemic, anesthetic, and other activities with a confidence of 73 to 93%. In addition, some of them can be used as inhibitors of cholesterol synthesis and show hepatoprotection properties. Phosphonosteroids demonstrate antineoplastic and antihypercholesterolemic activities with a certainty of 85 to 90%. And also, they can be used as ovulation inhibitors or female steroid contraceptives with confidence from 86 to 98%.

Peroxy steroids derived from plant and fungi and their biological activities

Peroxides represent a large and interesting group of biologically active natural compounds. All these metabolites contain a peroxide group (R-O-O-R). This review describes studies of more than 60 peroxides isolated from plants and fungi. Most of the plant peroxy steroids exhibit high antiprotozoal (Plasmodium) activity with a confidence of up to 95%, while steroids harvested from fungi show more antineoplastic activity with a confidence of up to 94%. In addition, more than 20 different activities of both groups of peroxides with a probability of 78 to 90% have also been predicted using computer program PASS.