Alexey A. Orlov

Progress in visual representations of chemical space.

Introduction: The concept of ‘chemical space’ reveals itself in two forms: the discrete set of all possible molecules, and multi-dimensional descriptor space encompassing all the possible molecules. Approaches based on this concept are widely used for the analysis and enumeration of compound databases, library design, and structure–activity relationships (SAR) and landscape studies. Visual representations of chemical space differ in their applicability domains and features and require expert knowledge for choosing the right tool for a particular problem. Areas covered: In this review, the authors present recent advances in visualization of the chemical space in the framework of current general understanding of this topic. Attention is given to such methods as van Krevelen diagrams, descriptor plots, principal components analysis (PCA), self-organizing maps (SOM), generative topographic mapping (GTM), graph and network-based approaches. Notable application examples are provided. Expert opinion: With the growth of computational power, representations of large datasets are becoming more and more common instruments in the toolboxes of chemoinformaticians. Every scientist in the field can find the method of choice for a particular task. However, there is no universal reference representation of the chemical space currently available and expert knowledge is required.

Rigid amphipathic nucleosides suppress reproduction of the tick-borne encephalitis virus

Rigid amphipathic fusion inhibitors (RAFIs), 5-arylethynyl uracil nucleosides with bulky aryl groups, appeared to have considerable activity against tick-borne encephalitis virus (TBEV) in cell culture. The rigid ethynyl linker and perylene residue are essential structural prerequisites for high activity, giving EC50 values of 18 and 24 nM for 5-(perylen-3-yl)ethynyl-arabino-uridine and 5-(perylen-3-yl)ethynyl-2′-deoxy-uridine, respectively, upon simultaneous mixing of the compounds, cells and virus.

Selective Inhibition of Enterovirus A Species Members’ Reproduction by Furano[2,3-d]pyrimidine Nucleosides Revealed by Antiviral Activity Profiling against (+)ssRNA Viruses

Abstract The rational design of broad‐spectrum antivirals requires data on antiviral activity of compounds against multiple viruses, which are often not available. We have developed a panel of (+)ssRNA viruses composed of Enterovirus and Flavivirus genera members allowing to study these activity spectra. Antiviral activity profiling of a set of nucleoside analogues revealed N 4‐hydroxycytidine as an efficient inhibitor of replication of coxsackieviruses and other enteroviruses, but ineffective against tick‐borne encephalitis virus. Furano[2, 3‐d]pyrimidine nucleosides with n‐pentyl or n‐hexyl tails showed selective inhibition of Enterovirus A representatives. 5‐(Tetradec‐1‐yn‐1‐yl)‐uridine showed selective inhibition of tick‐borne encephalitis virus at the micromolar level.

Novel water-soluble lignin derivative BP-Cx-1: identification of components and screening of potential targets in silico and in vitro

Identification of molecular targets and mechanism of action is always a challenge, in particular – for natural compounds due to inherent chemical complexity. BP-Cx-1 is a water-soluble modification of hydrolyzed lignin used as the platform for a portfolio of innovative pharmacological products aimed for therapy and supportive care of oncological patients. The present study describes a new approach, which combines in vitro screening of potential molecular targets for BP-Cx-1 using Diversity Profile - P9 panel by Eurofins Cerep (France) with a search of possible active components in silico in ChEMBL - manually curated chemical database of bioactive molecules with drug-like properties. The results of diversity assay demonstrate that BP-Cx-1 has multiple biological effects on neurotransmitters receptors, ligand-gated ion channels and transporters. Of particular importance is that the major part of identified molecular targets are involved in modulation of inflammation and immune response and might be related to tumorigenesis. Characterization of molecular composition of BP-Cx-1 with Fourier Transform Ion Cyclotron Resonance Mass Spectrometry and subsequent identification of possible active components by searching for molecular matches in silico in ChEMBL indicated polyphenolic components, nominally, flavonoids, sapogenins, phenanthrenes, as the major carriers of biological activity of BP-Cx-1. In vitro and in silico target screening yielded overlapping lists of proteins: adenosine receptors, dopamine receptor DRD4, glucocorticoid receptor, serotonin receptor 5-HT1, prostaglandin receptors, muscarinic cholinergic receptor, GABAA receptor. The pleiotropic molecular activities of polyphenolic components are beneficial in treatment of multifactorial disorders such as diseases associated with chronic inflammation and cancer.

Probing chemical space of tick‐borne encephalitis virus reproduction inhibitors with organoselenium compounds

Tick‐borne encephalitis virus (TBEV), a member of the genus Flavivirus, is the leading cause of arboviral neuroinfections in Europe. Only a few classes of the nucleoside and non‐nucleoside inhibitors were investigated against TBEV reproduction. Paving the way to previously unexplored areas of anti‐TBEV chemical space, we assessed the inhibition of TBEV reproduction in the plaque reduction assay by various compounds derived from cyanothioacetamide and cyanoselenoacetamide. Compounds from seven classes, including 4‐(alkylthio)‐2‐aryl‐3‐azaspiro[5.5]undec‐4‐ene‐1,1,5‐tricarbonitriles, 3‐arylamino‐2‐(selenazol‐2‐yl)acrylonitriles, ethyl 6‐(alkylseleno)‐5‐cyano‐2‐oxo‐1,2‐dihydropyridine‐3‐carboxylates, 6‐(alkylseleno)‐2‐oxo‐1,4,5,6‐tetrahydropyridine‐3‐carbonitriles, 2‐(alkylseleno)‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carbonitriles, 8‐selenoxo‐3,5,7,11‐tetraazatricyclo[7.3.1.02,7]tridec‐2‐ene‐1,9‐dicarbonitriles, and selenolo[2,3‐b]quinolines, inhibited TBEV reproduction with EC50 values in the micromolar range while showing moderate cytotoxicity and no inhibition of enterovirus reproduction. Thus, new scaffolds with promising anti‐TBEV activity were found.

Correction: Rigid amphipathic nucleosides suppress reproduction of the tick-borne encephalitis virus

Correction for ‘Rigid amphipathic nucleosides suppress reproduction of the tick-borne encephalitis virus’ by Alexey A. Orlov et al., MedChemComm, 2016, DOI: 10.1039/c5md00538h.