V. A. Potemkin

ToxAlerts: A Web Server of Structural Alerts for Toxic Chemicals and Compounds with Potential Adverse Reactions

The article presents a Web-based platform for collecting and storing toxicological structural alerts from literature and for virtual screening of chemical libraries to flag potentially toxic chemicals and compounds that can cause adverse side effects. An alert is uniquely identified by a SMARTS template, a toxicological endpoint, and a publication where the alert was described. Additionally, the system allows storing complementary information such as name, comments, and mechanism of action, as well as other data. Most importantly, the platform can be easily used for fast virtual screening of large chemical datasets, focused libraries, or newly designed compounds against the toxicological alerts, providing a detailed profile of the chemicals grouped by structural alerts and endpoints. Such a facility can be used for decision making regarding whether a compound should be tested experimentally, validated with available QSAR models, or eliminated from consideration altogether. The alert-based screening can also be helpful for an easier interpretation of more complex QSAR models. The system is publicly accessible and tightly integrated with the Online Chemical Modeling Environment (OCHEM, http://ochem.eu). The system is open and expandable: any registered OCHEM user can introduce new alerts, browse, edit alerts introduced by other users, and virtually screen his/her data sets against all or selected alerts. The user sets being passed through the structural alerts can be used at OCHEM for other typical tasks: exporting in a wide variety of formats, development of QSAR models, additional filtering by other criteria, etc. The database already contains almost 600 structural alerts for such endpoints as mutagenicity, carcinogenicity, skin sensitization, compounds that undergo metabolic activation, and compounds that form reactive metabolites and, thus, can cause adverse reactions. The ToxAlerts platform is accessible on the Web at http://ochem.eu/alerts, and it is constantly growing.

Molecular and crystal properties of ethyl 4,6‐dimethyl‐2‐thioxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carboxylate from experimental and theoretical electron densities

The electron density and electronic energy densities in ethyl 4,6-dimethyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate have been studied from accurate X-ray diffraction measurements at 110 K and theoretical single-molecule and periodic crystal calculations. The Quantum Theory of Atoms in Molecules and Crystals (QTAMC) was applied to analyze the electron-density and electronic energy-density features to estimate their reproducibility in molecules and crystals. It was found that the local electron-density values at the bond critical points derived by different methods are in reasonable agreement, while the Laplacian of the electron density computed from wavefunctions, and electron densities derived from experimental or theoretical structure factors in terms of the Hansen-Coppens multipole model differ significantly. This disagreement results from insufficient flexibility of the multipole model to describe the longitudinal electron-density curvature in the case of shared atomic interactions. This deficiency runs through all the existing QTAMC bonding descriptors which contain the Laplacian term. The integrated atomic characteristics, however, suffer noticeably less from the aforementioned shortcoming. We conclude that the electron-density and electronic energy QTAMC characteristics derived from wavefunctions, especially the integrated quantities, are nowadays the most suitable candidates for analysis of the transferability of atoms and atomic groups in similar compounds.

Principles for 3D/4D QSAR classification of drugs.

The principles for the 3D/4D classification of drugs are introduced in this article. Based on these principles, new techniques for the reconstruction of complementary selfconsistent receptor fields for the classification of drugs, taking into account their multitautomeric and multiconformational states, are created. The series of examples of classification of drugs by their activity (active or nonactive), by their mechanisms of action, by their target and binding site and by the most important stages of their action are given. Prospects for rational drug design are highlighted.

[4+2]-Cycloaddition of 3,6-bis(3,5-dimethyl-4-R-pyrazol-1-yl)-1,2,4,5-tetrazines with alkenes

A number of 1,4-dihydropyridazines and pyridazines were prepared by the Diels-Alder reaction with an inverse electron demand from cyclic heterodiene systems, 3,6-bis(3,5-dimethyl-4-R-pyrazol-1-yl)-1,2,4,5-tetrazines, and some enamines as well as from 4-vinylpyridine, butyl vinyl ether, phenylacetylene, and acrylamide. The reaction of 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine with styrene afforded 4,5-dihydropyridazine, which was readily oxidized by atmospheric oxygen to form the corresponding pyridazine. Electron-withdrawing substituents (Br or Cl) in the pyrazole rings accelerate [4+2]-cycloaddition. When heated, 1,4-dihydropyridazines, which were synthesized from tetrazines and enamines, eliminated amine to give pyridazines. The reactivities of tetrazines were evaluated by quantum-chemical methods.

Compressibility of Gas Hydrates

Experimental data on the pressure dependence of unit cell parameters for the gas hydrates of ethane (cubic structure I, pressure range 0-2 GPa), xenon (cubic structure I, pressure range 0-1.5 GPa) and the double hydrate of tetrahydrofuran+xenon (cubic structure II, pressure range 0-3 GPa) are presented. Approximation of the data using the cubic Birch-Murnaghan equation, P=1.5B(0)[(V(0)/V)(7/3)-(V(0)/V)(5/3)], gave the following results: for ethane hydrate V(0)=1781 Å(3) , B(0)=11.2 GPa; for xenon hydrate V(0)=1726 Å(3) , B(0)=9.3 GPa; for the double hydrate of tetrahydrofuran+xenon V(0)=5323 Å(3) , B(0)=8.8 GPa. In the last case, the approximation was performed within the pressure range 0-1.5 GPa; it is impossible to describe the results within a broader pressure range using the cubic Birch-Murnaghan equation. At the maximum pressure of the existence of the double hydrate of tetrahydrofuran+xenon (3.1 GPa), the unit cell volume was 86% of the unit cell volume at zero pressure. Analysis of the experimental data obtained by us and data available from the literature showed that 1) the bulk modulus of gas hydrates with classical polyhedral structures, in most cases, are close to each other and 2) the bulk modulus is mainly determined by the elasticity of the hydrogen-bonded water framework. Variable filling of the cavities with guest molecules also has a substantial effect on the bulk modulus. On the basis of the obtained results, we concluded that the bulk modulus of gas hydrates with classical polyhedral structures and existing at pressures up to 1.5 GPa was equal to (9±2) GPa. In cases when data on the equations of state for the hydrates were unavailable, the indicated values may be recommended as the most probable ones.

Theoretical Investigation of the Antituberculous Activity of Membranotropic Podands

The discovery of the antituberculous properties of streptomycin (in 1944), as well as of the same activity of isoniazid and pyrazinamide (in 1952), significantly increased the efficacy of chemotherapy in the treatment of tuberculosis and noticeably reduced the death rate caused by this disorder [1]. However, a new episode in the disease rate took place in 1985 [1] and, despite a large number of antituberculous drugs, the treatment of tuberculosis is among the main problems in modern medicine. This is explained primarily by the rapid development of drug resistance in Mycobacterium tuberculosis and by the high toxicity of the existing preparations [1, 2]. Therefore, creation of new, effective antituberculous drugs is an important current task. The multilayer membrane shell of tubercle bacillus is a serious obstacle to delivering drugs to targets. For this reason, a promising direction in the development of effective antituberculous preparations is the search for agents possessing a high ability to penetrate through cell membranes. In recent years, our research has been concentrated on the synthesis and characterization of macrocyclic polyesters and their noncyclic analogs – podands, possessing an increased ability to penetrate through biological membranes. Among these, there are compounds exhibiting high antituberculous activity [3 – 7]. Tables 1 – 3 present data on the structures of synthesized podands and on the antituberculous activity of these compounds expressed in terms of logarithms of the experimentally determined and calculated minimum inhibiting concentrations (lg MICexp and lg MICcalcd, respectively) for these compounds. Our preliminary analysis of these data revealed the following empirical relationships. (i) A high tuberculostatic activity is inherent in formyl podands I and II not containing clearly pronounced pharmacophore fragments. (ii) Hydrazones of semicarbazide and hydrazones of nicotinic and benzoic acid hydrazides acquire tuberculostatic activity in the form of the corresponding podands (compounds VII – XI, XIII – XV, XVII) [6]. (iii) Tuberculostatic activity increases by two orders in magnitude on passage from crown esters (compounds XXVI, XXVII) to podands representing their noncyclic analogs (compounds XXVIII – XXXIII) [4]. (iv) A comparison of the antibacterial activity of pefloxacin (fluoroquinolone antibiotic) and the corresponding fluoroquinolone podands (compounds XXXVII – XLVI) shows that the latter compounds exhibit significant selectivity with respect to Mycobacterium tuberculosis [5]. These results suggest that the polyester fragment of podands plays an important role in the action upon certain targets in the given bacterial species. In order to verify this assumption, we have theoretically studied the quantitative structure – activity relationship (QSAR) between the conformation of these compounds and their tuberculostatic properties. Calculations performed within the framework of the semiempirical quantum-chemical PM3 approximation showed that the most favorable structure is represented by the podand chain possessing a circular conformation (Fig. 1). This configuration provides for the parallel orientation of the planes of (hetero)aromatic rings on the ends of the podand chain and for the formation of a pseudocyclic structure due to the – interaction between these rings. This allows metal cations to be incorporated into a molecular cavity by forming donor – acceptor bonds with heteroatoms (nitrogen, oxygen, sulfur, etc.) present in the chain. This conclusion is consistent with data obtained by the IR and H NMR spectroscopic techniques for the structure of podand complexes with metal cations in chloroform solutions [8]. The complex formation in these systems is accompanied by considerable modification of the spectra of (hetero)aromatic fragments, while variations in the spectra of ethylene oxide fragments are minimal Pharmaceutical Chemistry Journal Vol. 37, No. 9, 2003

Theoretical investigation of the antituberculosis activity of compounds of the dihydropyrimidine series

An analysis of the tuberculostatic activity of dihydropyrimidine derivatives has been carried out using the 3D QSAR algorithm BiS/MC. Conformers responsible for the biological action of these compounds have been found and their complexes with receptors have been modeled. It is shown that oxygen atoms of the podand chain or ether group of most biologically active compounds interact with postiviely charged atoms of the receptor. Pharmacophore and antipharmacophore fragments have been identified. The relationship of the tuberculostatic activity and characteristics of the receptor-ligand complexes have been established (correlation coefficient, 0.99). The results can be used for directed synthesis of effective antituberculosis agents and for predicting the tuberculostatic activity of new compounds.

A Method for Multiconformational Modeling of the Three‐Dimensional Shape of a Molecule

A method for multiconformational modeling of the three‐dimensional shape of a molecule is proposed that includes search for conformers, their optimum superposition, and analysis of spatial features of the resulting structure. The method allows one to determine features of various molecular conformations of compounds under study, to assess the contributions of conformers to particular properties of the substance, to evaluate the space occupied by the molecule, and to compare the average size of the multiconformational model of the molecule with the sizes of the most stable conformations. The potentials of the model are illustrated by density calculations for 137 organic liquids.

Genetic Algorithm for Predicting Structures and Properties of Molecular Aggregates in Organic Substances

A genetic algorithm for predicting the structures and properties of molecular aggregates in organic substances is proposed. It has been used for modeling the most probable dimers and trimers existing in 137 organic liquids. It has been shown that the geometric and energetic features of modeled aggregates agree with known data. The energy of aggregation correlates with the enthalpy of evaporation of substances. The dependence of the energetic and geometric features of aggregates on the chemical nature of their constituent molecules is discussed.

Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information

The Online Chemical Modeling Environment is a unique platform on the Web that aims to automate and simplify the typical steps required for QSAR modeling. The platform consists of two major subsystems: the database of experimental measurements and the modeling framework. The database is user-contributed and contains a set of tools for easy input, search and modification of thousands of records. The OCHEM database is based on the wiki principle and focuses on data quality and verification. The database is tightly integrated with the modeling framework, which supports all the steps required to create a predictive model: data search, calculation and selection of a vast variety of molecular descriptors, application of machine learning methods, validation, analysis of the model and assessment of the applicability domain. Our intention is to make OCHEM an ultimate platform to perform the QSPR/QSAR studies online and share it with other users on the Web. The OCHEM is free for the web users and it is available online at http://ochem.eu. “Computing chemistry on the web” [1] is becoming a reality.