Generative Topographic Mapping Approach to Modeling and Chemical Space Visualization of Human Intestinal Transporters

© 2016, Springer Science+Business Media New York.The generative topographic mapping (GTM) approach has been used both to build predictive models linking chemical structure of molecules and their ability to bind some membrane transport proteins (transporters) and to visualize a chemical space of transporters’ binders on two-dimensional maps. For this purpose, experimental data on 2958 molecules active against up to 11 transporters have been used. It has been shown that GTM-based classification (active/inactive) models display reasonable predictive performance, comparable with that of such popular machine-learning methods as Random Forest, SVM, or k-NN. Moreover, GTM offers its own models applicability domain definition which may significantly improve the models performance. GTM maps themselves represent an interesting tool of the chemical space analysis of the transporters’ ligands. Thus, with the help of class landscapes, they identify distinct zones populated by active or inactive molecules with respect to a given transporter. As demonstrated in this paper, the superposition of class landscapes describing different activities delineates the areas mostly populated by the compounds of desired pharmacological profile

Complexes of podand-containing bis(dithiophosphonate) ligands with cobalt(II), nickel(II) and cadmium(II): Recognition of CH2Cl 2

Reaction of the potassium salts of podand-containing bis(dithiophosphonate) s [PhO(4-C6H4)P(S)(SH)OCH2CH2] 2O (H 2 L) with Co(II), Ni(II) and Cd(II) in aqueous EtOH leads to complexes of formulae M2(L-S,S')2. The structural formulae of the compounds were deduced by physico-chemical and spectroscopic methods. It was established that complex Ni 2 L 2 recognizes CH2Cl2. © 2008 Springer Science+Business Media B.V

Structure–reactivity modeling using mixture-based representation of chemical reactions

© 2017, Springer International Publishing AG. We describe a novel approach of reaction representation as a combination of two mixtures: a mixture of reactants and a mixture of products. In turn, each mixture can be encoded using an earlier reported approach involving simplex descriptors (SiRMS). The feature vector representing these two mixtures results from either concatenated product and reactant descriptors or the difference between descriptors of products and reactants. This reaction representation doesn’t need an explicit labeling of a reaction center. The rigorous “product-out” cross-validation (CV) strategy has been suggested. Unlike the naïve “reaction-out” CV approach based on a random selection of items, the proposed one provides with more realistic estimation of prediction accuracy for reactions resulting in novel products. The new methodology has been applied to model rate constants of E2 reactions. It has been demonstrated that the use of the fragment control domain applicability approach significantly increases prediction accuracy of the models. The models obtained with new “mixture” approach performed better than those required either explicit (Condensed Graph of Reaction) or implicit (reaction fingerprints) reaction center labeling

QSPR MODELING OF TAUTOMERIC EQUILIBRIA USING LOCAL DESCRIPTORS

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Structure–reactivity relationship in Diels–Alder reactions obtained using the condensed reaction graph approach

© 2017, Pleiades Publishing, Ltd. By the structural representation of a chemical reaction in the form of a condensed graph a model allowing the prediction of rate constants (logk) of Diels–Alder reactions performed in different solvents and at different temperatures is constructed for the first time. The model demonstrates good agreement between the predicted and experimental logk values: the mean squared error is less than 0.75 log units. Erroneous predictions correspond to reactions in which reagents contain rarely occurring structural fragments. The model is available for users at https://cimm.kpfu.ru/predictor/

Visualization and Analysis of Complex Reaction Data: The Case of Tautomeric Equilibria

© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Generative Topographic Mapping (GTM) approach was successfully used to visualize, analyze and model the equilibrium constants (KT) of tautomeric transformations as a function of both structure and experimental conditions. The modeling set contained 695 entries corresponding to 350 unique transformations of 10 tautomeric types, for which KT values were measured in different solvents and at different temperatures. Two types of GTM-based classification models were trained: first, a “structural” approach focused on separating tautomeric classes, irrespective of reaction conditions, then a “general” approach accounting for both structure and conditions. In both cases, the cross-validated Balanced Accuracy was close to 1 and the clusters, assembling equilibria of particular classes, were well separated in 2-dimentional GTM latent space. Data points corresponding to similar transformations measured under different experimental conditions, are well separated on the maps. Additionally, GTM-driven regression models were found to have their predictive performance dependent on different scenarios of the selection of local fragment descriptors involving special marked atoms (proton donors or acceptors). The application of local descriptors significantly improves the model performance in 5-fold cross-validation: RMSE=0.63 and 0.82 logKT units with and without local descriptors, respectively. This trend was as well observed for SVR calculations, performed for the comparison purposes

Complexes of N-thiophosphorylthiourea (EtO)2P(O)CH2C6H4-4-[NHC(S)NHP(S)(OiPr)2] with Zn(II), Cd(II), Co(II) and Cu(PPh3)(I)

Reaction of O,O'-diisopropylthiophosphoric acid isothiocyanate (iPrO)2P(S)NCS with diethyl 4-aminobenzylphosphonate (EtO)2P(O)CH2C6H4-4-NH2 leads to the new N-thiophosphorylated thiourea (EtO)2P(O)CH2C6H4-4-[NHC(S)NHP(S)(OiPr)2] (HL). Reaction of the potassium salt of HL with Zn(II), Cd(II) and Co(II) in aqueous EtOH leads to complexes of formula M(L-S,S')2 (ML2). Heteroligand copper(I) complex of HL and triphenylphosphine was prepared by the reaction of the potassium salt KL and Cu(PPh3)3I. Copper in complex Cu(PPh3)L is bound by one PPh3 and one SCNPS fragment of the chelating ligand. Compounds obtained were investigated by IR, UV-Vis, 1H and 31P{1H} NMR spectroscopy, and microanalysis. The structures of HL and Cu(PPh3)L were investigated by single crystal X-ray diffraction analysis. © 2008 Elsevier Ltd. All rights reserved

Monodentate S-vs. bidentate 1,5-O,S-coordination of N-phosphoryl-N′-(R)-thioureas with Pd(II)

Reaction of N-phosphorylated thioureas of common formula RNHC(S)NHP(O)(OiPr)2 (R = tBu, HLI; R = Ph, HLII; R = 4′-benzo-15-crown-5, HLIII) with Pd(PhCN)2Cl2 in acetonitrile leads to complexes of the structure Pd(HLI-S)2Cl2 (1), Pd(HLII-S)2Cl2 (2) and Pd(HLIII-S)2Cl2 (3). Reaction of N-phosphorylated thioureas of common formula RC(S)NHP(O)(OiPr)2 (R = Et2N, HLIV; R = morpholine-N-yl, HLV) in the same conditions leads to complexes Pd(LIV-O,S)2 (4) and Pd(LV-O,S)2 (5), where the palladium(II) atoms are coordinated in a square-planar fashion by the C{double bond, long}S sulfur atoms and the P{double bond, long}O oxygen atoms of two anionic ligands. The crystal structure of complex 1 has been investigated by X-ray crystallography. It was established that the thiourea ligands are in a trans-configuration and the palladium(II) cation is coordinated by the sulfur atoms of the C{double bond, long}S groups and the chlorine atoms. Complex 1 is the first example of palladium(II) complex in which the potentially chelating N-phosphorylated thiourea ligand is bound through the sulfur atom only. © 2008 Elsevier Ltd. All rights reserved

Complexes of N-thiophosphorylthiourea tBuNHC(S)NHP(S)(OiPr)2 with zinc(II), cadmium(II), nickel(II), and cobalt(II) cations

Reaction of the potassium salt of N-thiophosphorylthiourea tBuNHC(S)NHP(S)(OiPr)2 (HL) with ZnII, CdII, NiII and CoII in aqueous EtOH leads to complexes of common formula M(L-S,S′)2 (ML2). Complexes were investigated by IR, UV-Vis, 1H and 31P{1H} NMR spectroscopy and microanalysis The structure of complex NiL2 was investigated by single crystal X-ray diffraction analysis. The nickel(II) ion has a squre-planar environment, S4, with two anionic ligands involving 1,5-S,S′-coordination mode. The ligands are bound in a trans configuration. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA

Nickel(II) complexes with N-(thio)phosphorylthioureas AdNHC(S)NHP(X)(OiPr)2: Versatile coordination of phosphoryl (X = O) and thiophosphoryl (X = S) derivatives

The reaction of the potassium salts of N-(thio)phosphorylated thioureas of the common formula AdN(H)C(S)N(H)P(X)(OiPr)2 (X = O, HLI; X = S, HLII) with the Ni(II) cation in aqueous EtOH leads to [Ni(LI,II)2] chelate complexes. The molecular structures of the thioureas HLI,II and the complexes [Ni(LI-N,S)2] and [Ni(LII-S,S′)2] were elucidated by single crystal X-ray diffraction analysis, IR, 1H and 31P NMR spectroscopy and microanalysis. In the complex [Ni(LI)2], the metal center is found to be in a square-planar N2S2 environment formed by the C{double bond, long}S sulfur atoms and the P-N nitrogen atoms of two deprotonated LI ligands. The ligands are in a trans configuration. The Ni(II) atom in complex [Ni(LII)2], with the deprotonated thiourea LII, is coordinated in a square-planar fashion by the C{double bond, long}S and P{double bond, long}S sulfur atoms of two anionic ligands. The ligands are in a cis configuration. © 2008 Elsevier Ltd. All rights reserved