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This is a review article of Generative Topographic Mapping (GTM) – a non-linear dimensionality reduction technique producing generative 2D maps of high-dimensional vector spaces – and its specific applications in Drug Design (chemical space cartography, compound library design and analysis, virtual screening, pharmacological profiling, de novo drug design, conformational space & docking interaction cartography, etc.) Written by chemoinformaticians for potential users among medicinal chemists and biologists, the article purposely avoids all underlying mathematics. First, the GTM concept is intuitively explained, based on the strong analogies with the rather popular Self-Organizing Maps (SOMs), which are well established library analysis tools. GTM is basically a fuzzy-logics-based generalization of SOMs. The second part of the review, some of published GTM applications in drug design are briefly revisited.

International audience; The Virtual Screening (VS) study described herein aimed at detecting novel Bromodomain BRD4 binders and relied on knowledge from public databases (ChEMBL, REAXYS) to establish a battery of predictive models of BRD activity for in silico selection of putative ligands. Beyond the actual discovery of new BRD ligands, this represented an opportunity to practically estimate the actual usefulness of public domain "Big Data" for robust predictive model building. Obtained models were used to virtually screen a collection of 2 million compounds from the Enamine company collection. This industrial partner then experimentally screened a subset of 2992 molecules selected by the VS procedure for their high likelihood to be active. Twenty nine confirmed hits were detected after experimental testing, representing 1% of the selected candidates. As a general conclusion, this study emphasizes once more that public structure-activity databases are nowadays key assets in drug discovery. Their usefulness is however limited by the state-of-the-art knowledge harvested so far by published studies. Target-specific structure activity information is rarely rich enough, and its heterogeneity makes it extremely difficult to exploit in rational drug design. Furthermore, published affinity measures serving to build models selecting compounds to be experimentally screened may not be well correlated with the experimental hit selection criterion (in practice, often imposed by equipment constraints). Nevertheless, a robust 2.6-fold increase in hit rate with respect to an equivalent, random screening campaign showed that machine learning is able to extract some real knowledge in spite of all the noise in structure-activity data.

We describe SILIRID (Simple Ligand–Receptor Interaction Descriptor), a novel fixed size descriptor characterizing protein–ligand interactions. SILIRID can be obtained from the binary interaction fingerprints (IFPs) by summing up the bits corresponding to identical amino acids. This results in a vector of 168 integer numbers corresponding to the product of the number of entries (20 amino acids and one cofactor) and 8 interaction types per amino acid (hydrophobic, aromatic face to face, aromatic edge to face, H-bond donated by the protein, H-bond donated by the ligand, ionic bond with protein cation and protein anion, and interaction with metal ion). Efficiency of SILIRID to distinguish different protein binding sites has been examined in similarity search in sc-PDB database, a druggable portion of the Protein Data Bank, using various protein–ligand complexes as queries. The performance of retrieval of structurally and evolutionary related classes of proteins was comparable to that of state-of-the-art approaches (ROC AUC≈0.91). SILIRID can efficiently be used to visualize chemogenomic space covered by sc-PDB using Generative Topographic Mapping (GTM): sc-PDB SILIRID data form clusters corresponding to different protein types.

Three new extractants, namely bis(1,3-dihexyloxypropan-2-yl) phosphoric acid, bis(1,3-dioctyloxypropan-2-yl) phosphoric acid and bis(1,3-di-2-ethylhexyloxypropan-2-yl) phosphoric acid, were synthesized and tested in mixture with tri- n -octyl phosphine oxide (TOPO) in Isane IP 185 for the recovery of uranium (VI) from 5.3 mol L − 1 synthetic phosphoric acid and 30% wt P 2 O 5 industrial wet phosphoric acid. The results were compared with those previously obtained with bis(1,3-dibutoxypropan-2-yl) phosphoric acid (BiDiBOPP), under similar experimental conditions. The increase of the length of the alkyloxy chains of bis(1,3-dialkyloxypropan-2-yl) phosphoric acid is responsible for an increase of the distribution coefficients of both uranium (VI) and iron (III) whereas steric hindrance effect arising from the increase of branching improves the selectivity for uranium (VI) against iron (III). A quantitative relationship between the distribution coefficients of uranium (VI) measured for the series of 7 extractants and two molecular descriptors has been developed. This opens a way for computer-guided design of new phosphoryl-containing extractants.

A series of novel RGD mimetics containing phthalimidine fragment was designed and synthesized. Their antiaggregative activity determined by Born’s method was shown to be due to inhibition of fibrinogen binding to αIIbβ3. Molecular docking of RGD mimetics to αIIbβ3 receptor showed the key interactions in this complex, and also some correlations have been observed between values of biological activity and docking scores. The single crystal X-ray data were obtained for five mimetics.

The complex [ FeL 2 1 ](ClO4)2·H2O (1a) (L1 = 4-methyl-2,6-bis(1H-pyrazol-1-yl)pyrimidine) was synthesized by the reaction of Fe(ClO4)2·6H2O with new NNN-tridentate pyrazolylpyrimidine ligand L1 in MeOH/EtOH mixture. It is the first example of iron(II) spin crossover complexes with 2,4(6)-di(1H-pyrazol-1-yl)pyrimidines and manifests gradual spin transition centered around 150 K on the χMT versus T curve without hysteresis. A broad heat capacity anomaly with the maximum at 150 K was observed on the Cp(T) dependence, ΔtrsH = 5.50 kJ/mol and ΔtrsS = 42.0 J/(mol K). Surprisingly, the syntheses of iron(II) perchlorate compound with L1 performed in EtOH and iPrOH afford another modification of the complex, [ FeL 2 1 ](ClO4)2·H2O (1b), being high spin in the 78–300 K temperature range. The complexes with 2,4-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylpyrimidine (L2), [ FeL 2 2 ](ClO4)2·EtOH (2), [ FeL 2 2 ](CF3SO3)2 (3), [FeL2Cl2] 0.5H2O (4) and [FeL2(NCS)2] (5) were synthesized in EtOH solutions. They are in the high spin state within 78–300 K temperature range.

New heterometallic complexes of Co, Ni, and Zn containing [RuNO(NO2)4OH]2− anion as polydentate ligand were synthesized and described by X-ray structural analysis. The distorted octahedral coordination sphere of the nonferrous metal is composed of three oxygen atoms of phosphine oxide ligands and three oxygen atoms of bridging OH and NO2 groups from [RuNO(NO2)4OH]2−. High-level DFT calculations showed that the stability of Ru/M complexes is determined by the charge transfer from remote NO and NO2 groups of the ruthenium anion to M2+ and by the electrostatic interactions of M2+ with coordinating oxygen atoms of OH and two NO2 groups.

Human blood:air, human and rat tissue (fat, brain, liver, muscle, and kidney):air partition coefficients of a diverse set of organic compounds were correlated and predicted using structural descriptors by employing CODESSA-PRO and ISIDA programs. Four and five descriptor regression models developed using CODESSA-PRO were validated on three different test sets. Overall, these models have reasonable values of correlation coefficients (R2) and leave-one-out correlation coefficients ( R cv 2 ) : R2 = 0.881–0.983; R cv 2 = 0.826 – 0.962 . Calculations with ISIDA resulted in models based on atom/bond sequences involving two to three atoms with statistical parameters that were similar to those of models obtained with CODESSA-PRO (R2 = 0.911–0.974; R cv 2 = 0.831 – 0.936 ). A mixed pool of molecular and fragment descriptors did not lead to significant improvement of the models.

XPS, Fe Lα,β and Cu Lα,β X-ray emission and Fe L-, Cu L-, S L-edge and O K-edge absorption spectroscopies, Mossbauer spectroscopy and cyclic voltammetry were applied to study reacted surface layers of natural chalcopyrite, CuFeS 2 . The surfaces became metal-depleted after the anodic oxidation in 1 M HCl and the leaching in 1 M H 2 SO 4 +0.2 M Fe 2 (SO 4 ) 3 or 1 M HCl+0.4 M FeCl 3 solutions, with the sulfur excess and iron/copper ratio been higher in the last instance, and were enriched in copper after the electrochemical reduction. The electronic structures of the metal-deficient layers up to several tenths of micrometer thick were similar to that of chalcopyrite, except that the density of the highest occupied states depended on sulfur anions formed (predominant S 3 -anions after the ferric sulfate treatment, S 4 -anions after the ferric chloride leaching or the potential sweep to 0.9 V, etc.). The layers created by the preliminary oxidation had only a small effect on the chalcopyrite voltammetry. We suggest a new reaction mechanism considering a role of the surface changes, including disordering and Anderson localization of the electronic states.

Monoclinic and hexagonal pyrrhotites leached in 1 mol/L HCl and exposed to the air at 100% and ∼10% relative humidity for up to 5 months were studied using X-ray diffraction, Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), X-ray emission spectroscopy, Mossbauer spectroscopy, and electron paramagnetic resonance (EPR). The amorphous, nonequilibrium, iron-depleted layer (NL) produced by the leaching amounted to half of the residue mass and was composed of predominantly low-spin ferrous iron and polysulfide anions. Elemental sulfur and goethite were the only crystalline products of the NL decomposition. FTIR spectroscopy and XPS also revealed several sulfoxy species and, at low humidity, a small amount of ferric oxide. Neither alterations of the underlying pyrrhotite nor new iron sulfide phases (pyrite, pyrrhotite, etc.) crystallized from the amorphous NL were found. The NL decomposition was faster in the wet environment than in the dry one, and the oxidation of the NL was much more rapid than that of starting pyrrhotites. The intensity and quadruple split of the Mossbauer signal from the product (an isomer shift of 0.36 mm/s) were found to increase over the aging, indicating that the NL structure becomes more rigid and the singlet Fe(II) gradually converts to Fe(III). X-ray Fe Lα,β emission spectra showed the formation of intermediate, high-spin Fe(II) within the NL oxidized in the humid environment, but not in the dry air. No unpaired electron spins were detected by EPR; lines of paramagnetic Fe3+ appeared after the samples were aged in the dry air for 49 d and even later in the humid atmosphere. These phenomena are explained in terms of the formation of defects with negative correlation energy, similar to noncrystalline semiconductor chalcogenides, and of the fast electron exchange between the iron species, respectively. Mechanisms for reactions involved with the weathering of iron sulfides, which take into consideration the NL lattice elasticity, S-S and S-O bonding, oxygen incorporation, and oxidative and spin state of iron, are discussed. It is suggested in particular that the surface layer, strongly enriched in sulfur, as well as elemental sulfur and ferric oxyhydroxides, do not inhibit sulfide oxidation and acid production under weathering conditions, but the partially oxidized, disordered, nonstoichiometric layer may be passive.

Two groups of iron(II) complexes with 1,2,4-triazoles have been studied by XPS and Mossbauer spectroscopy. In the first group, iron atoms in the high spin state ( S =2) were considered, and in the second group, atoms in the low spin state ( S =0). Essential changes in the Fe 2p and Fe 3s spectra were observed in going from the one group of complexes to the other, whereas the N 1s spectra were unchanged. The Fe 2p 3/2 binding energy for the low spin state complexes was shown to be 708.3–708.8 eV, and for the high spin state 710.2–711.0 eV. In the Fe 2p and Fe 3s spectra of the high spin complexes, multiplet and satellite structures are revealed. As a result of the analysis of experimental XPS and Mossbauer chemical shifts, we conclude that the ionicity of Fe–N chemical bonds in the high and low spin complexes is connected to the higher occupation of the 4s orbitals of the iron atom in the second group of compounds.

Comparative ab initio (HF/6-31G ∗ and MP2/6-31G ∗ ) and semiempirical (AM1 and PM3) studies of pyrromethenone as a model of the non-hydrogen bonded part of biliverdin-related compounds have been performed. The structure and the relative energies of the conformational isomers formed by rotation around the single and double CC bonds of the methine bridge were calculated. It has been found that the geometry of the pyrromethenone molecule calculated at the MP2, HF and AM1 levels corresponds well with the X-ray data of 3,4-dimethyl-2,2′-pyrromethen-5(1 H )-one. The reliability of the AM1 method for the calculations of biliverdin-related molecules has been proven. Calculations of the ground state of octamethylbilindione and biliverdin IXα molecules as models of open-chain tetrapyrrolic chromophores have been carried out at the AM1 level. An analysis of the rotation barrier heights and the relative energies in a vacuum and in a chloroform solution has been performed on biliverdin-related molecules to estimate the energy and structure effects at the rotation around the C 5 C 6 single bond at the methine bridge.

Complexation of the p -t-butyl-calix[4]arene monoanion (L − ) with alkali metal cations (M + ) in acetonitrile has been studied experimentally using NMR spectroscopy and UV spectrophotometry, and computationally using molecular dynamics and free energy perturbation simulations. Experiment indicates that in polar solvents such as acetone and acetonitrile, all the cations form 1:1 complexes which have an exo (non-inclusive) structure, with stability constant values falling in the order Li + > Na + > K + > (Rb + ) > Cs + . This is in full accord with the calculations, which indicate that an endo structure, as found for CsL in the solid state and chloroform solution should only result when cation solvation energies are small. For Li + , there is experimental evidence for the formation of a 2:1 (metal/ligand) species but its exact nature is obscure. The cone conformation adopted by the monoanion both when free and complexed (as indicated by room temperature NMR spectroscopy) has been characterised by a single crystal X-ray structure determination of a salt containing a large, ‘non-coordinating’ cation, [N((CH 2 ) 3 CH 3 ) 4 ][ p -t-butyl-calix[4]arene] CH 3 CN.

Calix[4]arene-bis-crown ligands (L), conformationally locked in the 1,3-alternate conformation, display remarkable ionophoric properties with respect to alkali cations (M + ). Of particular interest is the large Cs + Na + binding selectivity displayed by calix[4]-bis-crown-6, in separating radioactive Cs + from nuclear waste. Based on Molecular Dynamics and Free Energy Perturbation simulations, we report a consistent comparison of Na + , K + , Rb + and Cs + complexes in four different solvents (water, methanol, acetonitrile and chloroform) and in the gas phase, in order to elucidate solvent effects on structures and stabilities of these complexes. We predict that Cs + is complexed by calix[4]-bis-crown-6 better than Na + in water and methanol and acetonitrile solutions, whereas in chloroform and in the gas phase, Na + is preferred. Also, calix[4]-bis-crown-5 hosts are predicted to bind selectively Na + in chloroform, but K + or Rb + in methanol. Additionally, our studies on calix[4]-bis-crown-6 involve: 1. (i) the effect of a picrate counterion on structures and selectivities; 2. (ii) the role played by the hydrophobic p-t-butyl substituents; 3. (iii) modelling of ditopic bis-cation 2M + complexes.

New complexes of iron(II) iodide and thiocyanate with 4-amino-1,2,4-triazole were synthesized. The complexes were characterized by magnetic measurements, reflection, Mossbauer and IR spectra. The coordination of iron(II) is discussed on the basis of these data. The compounds posses reversible thermochromism (colour change from white to pink) due to the spin transition 5 T 2 ⇌ 1 A 1 .

Using EXAFS, XANES and X-ray fluorescence spectroscopy it has been established that the sharp spin crossover in a series of polynuclear complexes of iron(II) with triazole and aminotriazole is accompanied by considerable changes in the spatial and electronic structure. The effect of electronic and structural parameters on the spin crossover temperature in compounds of iron(II) with aminotriazoles upon change of anion and upon magnetic dilution with zinc is discussed.