Algorithm for determination of the local similarity of molecules

An algorithm for seeking common structural fragments in compounds of different classes is developed. The algorithm allows for the molecular geometry and atomic characteristics, It may be used for recognition of compounds with properties associated with the local similarity of molecules such as ligand complementarity to a receptor. An example of seeking common structural elements for nondrug analgesics (para-acetamidophenol, acetylsalicylic acid, and amidopyrine) is given. I. I. Polzunov Altai State Technical University. Translated fromZhurnal Strukturnoi Khimii, Vol. 36, No. 6, pp. 1083–1087, November–December, 1995. Translated by L. Smolina     

Methods and algorithms for predicting the properties of chemical compounds by common fragments of molecular graphs

Methods and algorithms for predicting the properties of chemical compounds by common fragments of their molecular graphs are described. The prediction algorithms are based on determination of a measure of structural proximity (distance) between molecular graphs, which depends on the size of their common fragment. The prediction procedure involves the following steps: partitioning the property classes of the training sample compounds into subclasses of structurally similar compounds; seeking structurally typical compounds and their fragments in each subclass; classifying control compounds according to their distances from the training sample compounds or fragments of classes; forming a set of essential fragments of samples potentially responsible for the properties exhibited by the compounds. The algorithms were successfully tested in the BACC system for analyzing and classifying biologically active compounds designed at the Institute of Mathematics, Siberian Branch, Russian Academy of Sciences. S. L. Sobolev Institute of Mathematics, Siberian Branch, Russian Academy of Sciences. Translated fromZhurnal Strukturnoi Khimii, Vol. 39, No. 1, pp. 113–125, January–February, 1998.     

Evaluation of the relationship between spectral and structural similarity in IR spectroscopy

Representation of a structural formula of a compound as a complete set of nonisomorphic k-vertex (2 ≤k≤7) connected fragments is used to evaluate the structural similarity of compounds. The spectra and structures of spectrally or structurally alike compounds are compared statistically using a database containing 32,000 IR spectra and structures. This study reveals some tendencies typical for both full IR spectra and their abbreviated versions represented by sets of most characteristic peaks. Applicability of IR databases to spectrum simulation for compounds with a specified structure is justified statistically. A method is proposed for evaluating the efficiency of a search algorithm selecting structural analogs of the compound from an IR database according to the query spectrum. Translated fromZhurnal Strukturnoi Khimii, Vol. 41, No. 2, pp. 379–390, March–April, 2000.     

Geometrical design of ligands for spherical ions

New types of ligands for spherical ions have been designed as part of the molecular design strategy for supramolecular compounds. In particular, symmetric conformers of macrocycles, built of −(CH₂)_n−O−(n=3,4,5) fragments, which envelope the spherical ion in a complementary way, have been constructed. Alos, new types of “bracelentands” with different, “hardening” fragments are suggested. Using the molecular mechanics methods, the selectivity of complex formation of the ligands with respect to alkaline metal ions has been investigated. A. V. Bogatskii Physicochemical Institute, Ukrainian Academy of Sciences. Translated fromZhurnal Strukturnoi Khimii, Vol. 36, No. 5, pp. 879–883, September–October, 1995. Translated by L. Smolina     

Interpretation of IR spectra using complete sets of structure fragment compositions and an IR search system. 3. Analysis of large fragments

The results of identification of five-, six-, and seven-node fragments by the IR spectra of compounds are characterized by quantitative parameters: probability, reliability, and types of fragments. This analysis is carried out using the database containing more than 11,000 complete IR spectra and structures of organic compounds. It is analyzed how the fractions of correct fragments in the search result depend on the threshold occurrence and nonrandomness of fragment selection. Examples of statistical reliability of the revealed fragments are given. Translated fromZhumal Struktumoi Khimii, Vol. 38, No. 2, pp. 369–379, March–April, 1997.     

On the origin of Baeyer strain in molecules – an ab initio and DFT analysis

It is shown that destabilization energy of organic molecules containing small rings can be estimated by quasi–homodesmotic reactions involving acyclic “strain–free” counterparts. These destabilization energies E_s can be well reproduced at the HF level employing cc-pVTZ basis set, because the contributions of the electron correlation and ZPV energy practically cancel each other in most cases. A predominating factor leading to a decreased stability of molecules involving small ring fragments is given by the Ω bond bending or Baeyer strain. It leads to a dramatic decrease in the electron–nuclei attraction, which is a hallmark of the angular strain. Similar results are obtained by the DFT–B3LYP method. It is strongly pointed out that Baeyer strain cannot be singled out from the total destabilization energy in a precise quantitative way, since it is interlocked with other types of intramolecular interactions like the nonbonded repulsions, a significant increase in the stability of the CH bonds emanating from the small cyclic structures and by the σ–aromaticity or σ–antiaromaticity in three– and four–membered rings, respectively. Nevertheless, it is fair to say that Baeyer strain is the essential factor in determining decreased stability of small ring compounds and that the diminished electron–nuclear attraction is its characteristic signature at the global level. Dedicated to Professor Karl Jug on the occasion of his 65th birthday.     

Complete sets of fragment compositions of structures for ir spectrum interpretation using a database. 4. Forming the most probable hypothesis about the structure of the unknown

This paper offers a new approach to forming hypotheses about the structure of organic compounds. The approach uses the fragment compositions of the structures selected by seeking analogs of the IR spectrum of the compound in the database. Even with “noise” fragments, the whole set of revealed fragments may be used for generating the possible structures of the unknown due to the variety of intersecting fragments in the selected structures. Forming the most plausible hypothesis about the structure of the compound is treated in detail, and the results are shown on particular examples. Translated fromZhumal Strukturnoi Khimii, Vol. 38, No. 4, pp. 785–794, July–August, 1997.     

Molecular meccano for light-sensitive and light-emitting nanosized systems based on unsaturated and macrocyclic compounds

The review presents the results of the development of an universal approach to the molecular design of light-sensitive and light-emitting nanosized systems with desired properties based on unsaturated and macrocyclic compounds. Within the same class of compounds, various nanosized systems were constructed using a limited number of structural fragments. These nanosized systems are susceptible to all main types of photoprocesses, such as fluorescence, photodissociation, photoisomerization, photocycloaddition, photoelectrocyclization, excimer formation, charge-transfer complex formation, the formation of the twisted intramolecular charge-transfer state (TICT state), and the electron transfer. The use of photostructural transformations for controlling the complexation and mechanical movements in molecular devices and machines is discussed. The prospects of application of the new strategy are exemplified by the design of the previously unknown types of molecular switches, materials for optical chemosensors, optical data recording and storage media, photoswitchable molecular devices, and photocontrolled molecular machines. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1299–1323, July, 2008.     

Algorithm for estimating molecular dissymmetry

A simple criterion for estimating molecular dissymmetry and an algorithm of its calculation are suggested. Calculations are performed for compounds belonging to different point groups. The new molecular characteristic may be used to predict the magnitude and sign of optical rotation. Chelyabinsk State University. Translated fromZhurnal Strukturnoi Khimii, Vol. 39, No. 3, pp. 500–506, May–June, 1998.     

Structure-guided fragment-based<Emphasis Type="Italic"> in silico</Emphasis> drug design of dengue protease inhibitors

An in silico fragment-based drug design approach was devised and applied towards the identification of small molecule inhibitors of the dengue virus (DENV) NS2B-NS3 protease. Currently, no DENV protease co-crystal structure with bound inhibitor and fully formed substrate binding site is available. Therefore a homology model of DENV NS2B-NS3 protease was generated employing a multiple template spatial restraints method and used for structure-based design. A library of molecular fragments was derived from the ZINC screening database with help of the retrosynthetic combinatorial analysis procedure (RECAP). 150,000 molecular fragments were docked to the DENV protease homology model and the docking poses were rescored using a target-specific scoring function. High scoring fragments were assembled to small molecule candidates by an implicit linking cascade. The cascade included substructure searching and structural filters focusing on interactions with the S1 and S2 pockets of the protease. The chemical space adjacent to the promising candidates was further explored by neighborhood searching. A total of 23 compounds were tested experimentally and two compounds were discovered to inhibit dengue protease (IC₅₀ = 7.7 μM and 37.9 μM, respectively) and the related West Nile virus protease (IC₅₀ = 6.3 μM and 39.0 μM, respectively). This study demonstrates the successful application of a structure-guided fragment-based in silico drug design approach for dengue protease inhibitors providing straightforward hit generation using a combination of homology modeling, fragment docking, chemical similarity and structural filters.     

Ab initio investigation of the electronic structure of malonic dialdehyde derivatives

An ab initio quantum chemical investigation is performed for a series of ligands of Β-diketonate metal complexes: neutral and anionic forms of malonic dialdehyde and its nitrous analogs. The nature and sequence of molecular orbitals are established, and the influence of the basis set used on the results of electronic structure calculations of the compounds are analyzed. The electronic effects of oxygen substitution by the NH group are analyzed. The results are compared with the photoelectron spectroscopy data of the ligands. Translated fromZhurnal Strukturnoi Khimii, Vol. 38, No. 6, pp. 1061–1066, November–December, 1997.     

Co(II) and Cu(II) Schiff base complexes of bis(<Emphasis Type="Italic">N</Emphasis>-(4-diethylamino-2-methylphenyl)-3,5-di-<Emphasis Type="Italic">tert</Emphasis>-butylsalicylaldimine): Electrochemical and X-ray structural study

Copper(II) and cobalt(II) complexes of salicylaldimine obtained by the condensation of N,N-diethyl-2-methyl-1,4-phenylenediamine with 3,5-di-tert-butyl-2-hydroxybenzaldehyde have been synthesized and characterized by elemental analyses, magnetic susceptibility measurements, cyclic voltammetry, and FT-IR and UV–Vis spectroscopy. The molecular structure of the title copper(II) complex was determined by the single crystal X-ray diffraction technique. The Cu(II) center is coordinated by four atoms of the donor set in a compressed tetrahedral trans-[N₂O₂] environment, which can be essentially ascribed to the presence of bulky fragments of the ligand. The computed bond valences of the copper verify +2 oxidation state and indicate that the copper bonds, in particular Cu–N bonds, are elongated due to steric effects from bulky substituents in the ligands, N-(4-diethylamino-2-methylphenyl). Intermolecular C–H···π interactions leading to centrosymmetric synthons serve to stabilize periodic organization of the molecules.     

Universality behaviour for polarity formation in channel-type inclusion compounds

A statistical investigation based on a Markov chain theory of polarity formation applied to channel-type inclusion compounds loaded with both dipolar A–π–D and non-polar N–π–N (N: A or D) guests is presented. The key parameters effecting polarity formation are identified and their effects are explored. A number of paradoxes are set out and an attempt to explain the mechanisms behind them is made: dependence of macroscopic polarity on orientational selectivity induced by intermolecular interactions, tuning of polarity through (i) the concentration of non-polar guest and (ii) growth temperature. An erratum to this article can be found at     

Interpretation of IR spectra using complete sets of fragment compositions and an ir search system. 2. Determination of microfragment compositions of organic compounds

Identification of fragments of organic compounds by the IR spectra of the latter using complete sets of fragments and an IR database of more than 11,000 complete spectra and structures of organic compounds is treated. Probability and reliability of identification are estimated, and types of revealed fragments are examined. For many fragments, automatic identification is possible. The influence of the threshold and nonrandom occurrences of the fragment in the resulting list of structures on the efficiency of identification are considered. The reliability of identification is justified statistically. Translated fromZhurnal Struktumoi Khimii, Vol. 38, No. 1, pp. 155–166, January–February, 1997.     

A machine learning approach to computer-aided molecular design

Summary Preliminary results of a machine learning application concerning computer-aided molecular design applied to drug discovery are presented. The artificial intelligence techniques of machine learning use a sample of active and inactive compounds, which is viewed as a set of positive and negative examples, to allow the induction of a molecular model characterizing the interaction between the compounds and a target molecule. The algorithm is based on a twofold phase. In the first one — the specialization step — the program identifies a number of active/inactive pairs of compounds which appear to be the most useful in order to make the learning process as effective as possible and generates a dictionary of molecular fragments, deemed to be responsible for the activity of the compounds. In the second phase — the generalization step — the fragments thus generated are combined and generalized in order to select the most plausible hypothesis with respect to the sample of compounds. A knowledge base concerning physical and chemical properties is utilized during the inductive process.     

Stalis: A Computational Method for Template-Based Ab Initio Ligand Design

Proteins interact with small molecules through specific molecular recognition, which is central to essential biological functions in living systems. Therefore, understanding such interactions is crucial for basic sciences and drug discovery. Here, we present S tructure t emplate-based a b initio li gand design s olution (Stalis), a knowledge-based approach that uses structure templates from the Protein Data Bank libraries of whole ligands and their fragments and generates a set of molecules (virtual ligands) whose structures represent the pocket shape and chemical features of a given target binding site. Our benchmark performance evaluation shows that ligand structure-based virtual screening using virtual ligands from Stalis outperforms a receptor structure-based virtual screening using AutoDock Vina, demonstrating reliable overall screening performance applicable to computational high-throughput screening. However, virtual ligands from Stalis are worse in recognizing active compounds at the small fraction of a rank-ordered list of screened library compounds than crystal ligands, due to the low resolution of the virtual ligand structures. In conclusion, Stalis can facilitate drug discovery research by designing virtual ligands that can be used for fast ligand structure-based virtual screening. Moreover, Stalis provides actual three-dimensional ligand structures that likely bind to a target protein, enabling to gain structural insight into potential ligands. Stalis can be an efficient computational platform for high-throughput ligand design for fundamental biological study and drug discovery research at the proteomic level. © 2019 Wiley Periodicals, Inc.     

Monitoring industrial wastewater by online GC-MS with direct aqueous injection

An online GC–MS-system for automated monitoring of crude wastewater at a complex chemical production site is presented. The modular system is, in principal, based on commercial equipment, but utilizes a special, two-stage injector, which consists of a splitless vaporization chamber on top of a PTV injector filled with Tenax. This set-up enables direct injection of wastewater. Almost 140 volatile and semi-volatile compounds are calibrated down to 1 mg L⁻¹, which is sufficient for analysis of the influent of the wastewater-treatment plant. Two instruments analyze alternately, every 20 min, and the instrument cycle time is 40 min. The quantitative results are transferred to a database which is connected to a process-control system. Depending on the nature and concentration of a compound, an alarm can be generated and the wastewater stream can be diverted into an “off spec tank” if necessary. The GC–MS-system operates quasi-continuously with a system availability >98%. Data quality is automatically controlled in each run and by daily analysis of a quality-control sample. The development of a novel stacked PTV–PTV injector design to expand the range of analytes to selected basic compounds is described.     

Exploring fragment spaces under multiple physicochemical constraints

We present a new algorithm for the enumeration of chemical fragment spaces under constraints. Fragment spaces consist of a set of molecular fragments and a set of rules that specifies how fragments can be combined. Although fragment spaces typically cover an infinite number of molecules, they can be enumerated in case that a physicochemical profile of the requested compounds is given. By using min-max ranges for a number of corresponding properties, our algorithm is able to enumerate all molecules which obey these properties. To speed up the calculation, the given ranges are used directly during the build-up process to guide the selection of fragments. Furthermore, a topology based fragment filter is used to skip most of the redundant fragment combinations. We applied the algorithm to 40 different target classes. For each of these, we generated tailored fragment spaces from sets of known inhibitors and additionally derived ranges for several physicochemical properties. We characterized the target-specific fragment spaces and were able to enumerate the complete chemical subspaces for most of the targets.     

Taxonomy of Structures Selected from the IR Spectroscopy Database

This paper reports on taxonomy of the structural formulas of organic compounds selected from an IR spectroscopy database (DB) based on the similarity between the query spectrum and DB spectra. Two molecular graph models are compared: connectivity matrix and vector representation (exhaustive set of nonisomorphic connected k-vertex fragments). In both cases, taxonomy according to the shortest distance framework of the distance graph gives a classification of structural analogs into groups (taxons). An analysis of IR spectra and common subgraphs in the respective groups of graphs reveals large structural fragments of the compounds.