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Основой современного поиска новых лекарственных препаратов является анализ информации о механизмах возникновения заболевания, молекулярных мишенях и фармакологических веществах, действие которых позволяет нормализовать патологический процесс. Наряду с многочисленными информационными биомедицинскими и химическими базами данных, в последнее время появилось большое число вычислительных ресурсов, позволяющих прогнозировать физико-химические свойства, биологическую активность, токсичность, метаболизм и другие характеристики органических соединений на ранних стадиях разработки лекарств. Легкость доступа к этой информации через всемирную сеть Интернет существенно расширяет возможности исследователя и одновременно ставит перед ним задачу выбора информационных и вычислительных ресурсов, наиболее адекватных поставленным задачам. В работе представлен обзор свободно-доступных через Интернет биомедицинских и химических веб-ресурсов и предложены рекомендации по их оптимальному использованию на различных стадиях поиска и разработки более эффективных и безопасных лекарственных средств.

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/.

The bihelical (figure of "infinity") topology was examined from vantages of design, crystal structures, chirality, circular dichroism (CD) studies and molecular-orbital calculations. The minimalistic design envisaged the sequential linking of cystine to the anchor diphenic acid, which proved to be a general conformational lock. The bihelical compound 4 was obtained in two steps from diphenic anhydride 1 and cystine di-OMe. The chirality of 4 arises largely from the L-cystine. The bihelical compound 5 obtained from D-cystine di-OMe was found, by X-ray crystallography, CD studies, and optical rotation, to be the perfect mirror image of 4 prepared from L-cystine. The crystal structure of prototype 8, prepared by protocols used for 4 from the achiral cystine analogue cystamine, had a "U"-shaped conformation held together by intramolecular hydrogen bonds. Analysis of 4 and 5 show that the pairs of nine-membered beta-turn-like constructs made compact through hydrogen bonding with DMSO hold the key for the bihelical conformation. Another factor is the need for the presence of a ligand at the Calpha position. The absence of this, as in 8, allows major flexibility in the torsional angles around this critical region, promoting flexible alternatives. The CD analysis of 4, confirmed to be bihelical by X-ray crystallography, showed a typical negative band at about 210 A attributed to the beta-turn-like motif, and in the positive-band region a peak at about 227 A, generally related to the twist of the biphenyl unit. The cystamine analogue 8, which showed a "U"-type structure, presented a CD spectrum with no typical features. The total energy, derived from theoretical calculations by using the X-ray structure data, support the bihelical structure for 4 and a "U"-shaped one for 8. The limited utility of such calculations was tested with composite 9. Composite 9, in which the anchor diphenic acid is linked to cystamine on the one hand and to cystine on the other, showed a CD spectrum similar to that of 4, and this coupled with molecular-orbital calculations, using data from 4 and 8, predict a bihelical structure for this compound.