Probing the Isolobal Relation between Cp'''NiP3 and White Phosphorus by Experimental Charge Density Analysis.

An in-depth analysis of the description of bonding within Cp'''Ni-cyclo-P3 (Cp'''=1,2,4-tri-tert-butylcyclopentadienyl, [Ni]P3) employing X-ray diffraction based multipolar modeling, density functional theory (DFT) as well as an "experimental wavefunction" obtained from X-ray restrained wavefunction (XRW) fitting is presented. The results are compared to DFT calculations on white phosphorus - an isolobal analogue to [Ni]P3. A complementary bonding analysis shows insights into the reactivity of [Ni]P3. The isolobal principle is reflected in every aspect of our analysis and the employed methods seamlessly predict the differences in reactivity of [Ni]P3 and P4. Crystallographic modeling, solid-state NMR, and DFT calculations describe the dynamic behavior of the cyclo-P3 unit in the title molecule.

Racemic cis-bis-[bis-(pyrimidin-2-yl)amine-κN]bis(dicyanamido-κN1)iron(II) dihydrate: synthesis, crystal structure and Hirshfeld surface analysis.

The title compound, [Fe(C2N3)2(C8H7N5)2]·2H2O, has been synthesized solvothermally and characterized by single-crystal X-ray diffraction. The octa-hedral iron coordination polyhedron contains two di(pyrimidin-2-yl)amine ligands coordinated in a bidentate fashion, and two monodentate dicyanimido ligands, each coordinated via a terminal N atom, with the latter in a cis orientation. The ligand configuration about the iron atom is chiral, although the compound crystallizes as a racemic mixture: the Fe-N distances (> 2.07 Å) are characteristic of high-spin iron(II). In the crystal, an extensive series of N-H⋯N, O-H⋯N and O-H⋯O hydrogen bonds links the independent mol-ecular components into a three-dimensional framework. The H atoms of both water mol-ecules are disordered. The structure also features some π-π and anion-π inter-actions. The inter-molecular inter-actions were investigated by Hirshfeld surface analysis and two-dimensional fingerprint plots. Comparisons are made with some related compounds.

New Crystal Form of Human Neuropilin-1 b1 Fragment with Six Electrostatic Mutations Complexed with KDKPPR Peptide Ligand.

Neuropilin 1 (NRP1), a cell-surface co-receptor of a number of growth factors and other signaling molecules, has long been the focus of attention due to its association with the development and the progression of several types of cancer. For example, the KDKPPR peptide has recently been combined with a photosensitizer and a contrast agent to bind NRP1 for the detection and treatment by photodynamic therapy of glioblastoma, an aggressive brain cancer. The main therapeutic target is a pocket of the fragment b1 of NRP1 (NRP1-b1), in which vascular endothelial growth factors (VEGFs) bind. In the crystal packing of native human NRP1-b1, the VEGF-binding site is obstructed by a crystallographic symmetry neighbor protein, which prevents the binding of ligands. Six charged amino acids located at the protein surface were mutated to allow the protein to form a new crystal packing. The structure of the mutated fragment b1 complexed with the KDKPPR peptide was determined by X-ray crystallography. The variant crystallized in a new crystal form with the VEGF-binding cleft exposed to the solvent and, as expected, filled by the C-terminal moiety of the peptide. The atomic interactions were analyzed using new approaches based on a multipolar electron density model. Among other things, these methods indicated the role played by Asp320 and Glu348 in the electrostatic steering of the ligand in its binding site. Molecular dynamics simulations were carried out to further analyze the peptide binding and motion of the wild-type and mutant proteins. The simulations revealed that specific loops interacting with the peptide exhibited mobility in both the unbound and bound forms.

Deciphering the driving forces in crystal packing by analysis of electrostatic energies and contact enrichment ratios.

Hirshfeld surface analysis is a widely used tool for identifying the types of intermolecular contacts that contribute most significantly to crystal packing stabilization. One useful metric for analyzing these contacts is the contact enrichment descriptor, which indicates the types of contacts that are over- or under-represented. In this statistical study, enrichment ratios were combined with electrostatic energy (Eelec) data for a variety of compound families. To compute the electrostatic interaction energy between atoms, charge density models from the ELMAM2 database of multipolar atoms were used. As expected, strong hydrogen bonds such as O/N-H...N and O/N-H...O typically display large enrichment values and have the most negative (i.e. favorable) electrostatic energies. Conversely, contacts that are repulsive from an electrostatic perspective are usually the most under-represented. Analyzing the enrichment ratio and electrostatic energy indicators was shown to help identify which favorable contacts are the most competitive with each other. For weaker interactions, such as hydrophobic contacts, the behavior is less clear cut and can depend on other factors such as the chemical content of the molecule. The anticorrelation between contact enrichment and Eelec is generally lost for weaker contacts. However, we observed that C...C contacts are often enriched in crystal structures containing heterocycles, despite the low electrostatic attraction. For molecules with only weak hydrogen bond donors/acceptors and hydrophobic groups, the correlation between contact enrichment and Eelec is still evident for the strongest of these interactions. However, there are some exceptions where the most favorable contacts from an electrostatic perspective are not the most over-represented. This can occur in cases where the shape of the molecule is complex or elongated, favoring dispersion forces and shape complementarity in the packing.

Synthesis, crystal structure and Hirshfeld surface analysis of tert-butyl N-acetyl-carbamate.

This article reports a practical synthesis of tert-butyl acetyl-carbamate, C7H13NO3, from N-Boc-thio-acetamide and the study of its crystal structure. The reaction proceeds in the presence of natural phosphate as a catalyst, with excellent yield, simple workup and benign environment. The crystal structure was refined using a transferred multipolar atom model. In the crystal, symmetrical pairs of strong N-H⋯O hydrogen bonds connect the mol-ecules into dimers with an R 2 2(8) ring motif. The inter-actions between neighbouring dimers are mostly van der Waals, between hydro-phobic methyl groups. Hirshfeld surface analysis shows the major contributions to the crystal packing are from H⋯H (42.6%) and O⋯H (26.7%) contacts.

Theoretical search of crystal polymorphs of temozolomide.

Possible polymorphic forms of the chemotherapy drug, temozolomide were predicted from the ab initio and DFT methods. The lattice minimization via distributed multipole analysis was carried out for the hypothetical generated structures. A crystal with unit cell parameters close to the real one and of same space group was retrieved, with partly similar packing and interactions. The analysis of inter molecular interaction (through Hirshfeld surface) and electrostatic potential reveals the complementary sites in the molecule. The 26 predicted structures were analyzed with respect to two computed lattice energies and hydrogen-bond propensity. The lattice energy of the real crystal [EXP] packing ranked number 6 compared on the basis of DMACRYS software and number 3 on the basis of the total lattice energy issued from the Crystalexplorer17 software at the B3LYP/6-31G∗∗ level of theory. The molecule has two strong hydrogen bond donors and five strong acceptors. The predicted packings are stabilized by one or two strong N-H…O/N-H…N as well as weak C-H…O/C-H…N and H…π hydrogen bonds. While the real structure with Z' = 1, EXP, forms only one strong H-bond (N-H…O=C), several of the predicted packings form two strong H-bonds. Two predicted crystal packings have unit cell parameters close to the real structure, one of them shares several common intermolecular interactions.

Probing the Electronic Properties and Interaction Landscapes in a Series of N-(Chlorophenyl)pyridinecarboxamides.

A 3 × 3 isomer grid of nine N-(chlorophenyl)pyridinecarboxamides (NxxCl) is reported with physicochemical studies and single crystal structures (Nx = pyridinoyl moiety; xCl = aminochlorobenzene ring; x = para-/meta-/ortho-), as synthesized by the reaction of the substituted p-/m-/o-pyridinecarbonyl chlorides (Nx) with p-/m-/o-aminochlorobenzenes (xCl). Several of the nine NxxCl crystal structures display structural similarities with their halogenated NxxX and methylated NxxM relatives (x = p-/m-/o-substitutions; X = F, Br; M = methyl). Indeed, five of the nine NxxCl crystal structures are isomorphous with their NxxBr analogues as the NpmCl/Br, NpoCl/Br, NmoCl/NmoBr, NopCl/Br, and NooCl/Br pairs. In the NxxCl series, the favored hydrogen bonding mode is aggregation by N-H···Npyridine interactions, though amide···amide intermolecular interactions are noted in NpoCl and NmoCl. For the NoxCl triad, intramolecular N-H···Npyridine interactions influence molecular planarity, whereas NppCl·H2O (as a monohydrate) exhibits O-H···O, N-H···O1W, and O1W-H···N interactions as the primary hydrogen bonding. Analysis of chlorine-containing compounds on the CSD is noted for comparisons. The interaction environments are probed using Hirshfeld surface analysis and contact enrichment studies. The melting temperatures (T m) depend on both the lattice energy and molecular symmetry (Carnelley's rule), and the melting points can be well predicted from a linear regression of the two variables. The relationships of the T m values with the total energy, the electrostatic component, and the strongest hydrogen bond components have been analyzed.

π-Hole bonding in a new co-crystal hydrate of gallic acid and pyrazine: static and dynamic charge density analysis.

A new cocrystal hydrate of gallic acid with pyrazine (4GA, Py, 4H2O; GA4PyW4) was obtained and characterized by single crystal X-ray diffraction. In addition to structure determination, experimental charge density analysis was carried out in terms of Multipole Modelling (MP), X-ray wavefunction refinement (XWR) and maximum entropy method (MEM). As a part of XWR, the structural refinement via Hirshfeld atom refinement was carried out and resulted in O-H bond lengths close to values from neutron diffraction. A systematic comparison of molecular conformations and aromatic interactions in this new cocrystal hydrate was performed with other existing polymorphs of gallic acid. In GA4PyW4, the two symmetry-independent gallic acid molecules have a syn COOH orientation and form the common (COOH)2 dimeric synthon. The carboxyl C atom displays the characteristics of π-holes with electropositive regions above and below the molecular plane and engages in acceptor-donor interactions with oxygen atoms of acidic O-H groups and phenol groups of neighbouring gallic acid molecules. The signature of the π-hole was identified from experimental charge density analysis, both in static density maps in MP and XWR as well as dynamic density in MEM, but it cannot be pinned down to a specific atom-atom interaction. This study presents the first comparison between an XWR and a MEM experimental electron-density determination.

The Coordination Behavior of Two New Complexes, [(C7H10NO2)CdCl3]n(I) and [(C7H9NO2)CuCl2] (II), Based on 2,6-Dimethanolpyridine; Elaboration of the Structure and Hirshfeld Surface, Optical, Spectroscopic and Thermal Analysis.

Two novel complexes, [(C7H10NO2)CdCl3]n(I) and [(C7H9NO2)CuCl2],havebeen synthesized and characterized. Single crystal X-ray diffraction revealed that in compound (I), 2,6-dimethanol pyridinium acts as a monodentate ligand through the O atom of the hydroxyl group. Contrarily, the 2,6-dimethanol pyridine ligand interacts tridentately with the Cu(II) ion via the nitrogen atoms and the two oxygen (O, O') atoms of the two hydroxyl groups. The structure's intermolecular interactions were studied using contact enrichment ratios and Hirshfeld surfaces. Following metal coordination, numerous hydrogen connections between entities and parallel displacement stacking interactions between pyridine rings dictate the crystal packing of both compounds. The aromatic cycles generate layers in the crystal for both substances. Powder XRD measurements confirmed the crystalline sample phase purity. SEM confirmed the surface homogeneity, whereas EDX semi-quantitative analysis corroborated the composition. IR spectroscopy identified vibrational absorption bands, while optical UV-visible absorption spectroscopy investigated optical properties. The thermal stability of the two materials was tested using TG-DTA.

Machine learning-driven identification of drugs inhibiting cytochrome P450 2C9.

Cytochrome P450 2C9 (CYP2C9) is a major drug-metabolizing enzyme that represents 20% of the hepatic CYPs and is responsible for the metabolism of 15% of drugs. A general concern in drug discovery is to avoid the inhibition of CYP leading to toxic drug accumulation and adverse drug-drug interactions. However, the prediction of CYP inhibition remains challenging due to its complexity. We developed an original machine learning approach for the prediction of drug-like molecules inhibiting CYP2C9. We created new predictive models by integrating CYP2C9 protein structure and dynamics knowledge, an original selection of physicochemical properties of CYP2C9 inhibitors, and machine learning modeling. We tested the machine learning models on publicly available data and demonstrated that our models successfully predicted CYP2C9 inhibitors with an accuracy, sensitivity and specificity of approximately 80%. We experimentally validated the developed approach and provided the first identification of the drugs vatalanib, piriqualone, ticagrelor and cloperidone as strong inhibitors of CYP2C9 with IC values <18 µM and sertindole, asapiprant, duvelisib and dasatinib as moderate inhibitors with IC50 values between 40 and 85 µM. Vatalanib was identified as the strongest inhibitor with an IC50 value of 0.067 µM. Metabolism assays allowed the characterization of specific metabolites of abemaciclib, cloperidone, vatalanib and tarafenacin produced by CYP2C9. The obtained results demonstrate that such a strategy could improve the prediction of drug-drug interactions in clinical practice and could be utilized to prioritize drug candidates in drug discovery pipelines.

A rush to explore protein-ligand electrostatic interaction energy with Charger.

The mutual penetration of electron densities between two interacting molecules complicates the computation of an accurate electrostatic interaction energy based on a pseudo-atom representation of electron densities. The numerical exact potential and multipole moment (nEP/MM) method is time-consuming since it performs a 3D integration to obtain the electrostatic energy at short interaction distances. Nguyen et al. [(2018), Acta Cryst. A74, 524-536] recently reported a fully analytical computation of the electrostatic interaction energy (aEP/MM). This method performs much faster than nEP/MM (up to two orders of magnitude) and remains highly accurate. A new program library, Charger, contains an implementation of the aEP/MM method. Charger has been incorporated into the MoProViewer software. Benchmark tests on a series of small molecules containing only C, H, N and O atoms show the efficiency of Charger in terms of execution time and accuracy. Charger is also powerful in a study of electrostatic symbiosis between a protein and a ligand. It determines reliable protein-ligand interaction energies even when both contain S atoms. It easily estimates the individual contribution of every residue to the total protein-ligand electrostatic binding energy. Glutathione transferase (GST) in complex with a benzophenone ligand was studied due to the availability of both structural and thermodynamic data. The resulting analysis highlights not only the residues that stabilize the ligand but also those that hinder ligand binding from an electrostatic point of view. This offers new perspectives in the search for mutations to improve the interaction between the two partners. A proposed mutation would improve ligand binding to GST by removing an electrostatic obstacle, rather than by the traditional increase in the number of favourable contacts.

Charge density studies of multicentre two-electron bonding of an anion radical at non-ambient temperature and pressure.

The variation of charge density of two-electron multicentre bonding (pancake bonding) between semi-quinone radicals with pressure and temperature was studied on a salt of 5,6-di-chloro-2,3-di-cyano-semi-quinone radical anion (DDQ) with 4-cyano-N-methyl-pyridinium cation (4-CN) using the Transferable Aspheric Atom Model (TAAM) refinement. The pancake-bonded radical dimers are stacked by non-bonding π-interactions. With rising pressure, the covalent character of interactions between radicals increases, and above 2.55 GPa, the electron density indicates multicentric covalent interactions throughout the stack. The experimental charge densities were verified and corroborated by periodic DFT computations. The TAAM approach has been tested and validated for atomic resolution data measured at ambient pressure; this work shows this approach can also be applied to diffraction data obtained at pressures up to several gigapascals.

Correction: Synthesis, crystal structure and antibacterial studies of dihydropyrimidines and their regioselectively oxidized products.

[This corrects the article DOI: 10.1039/D0RA10255E.].

Morphology of the GdVO4 crystal: first-principles studies.

The present paper reports a theoretical investigation based on first-principles density functional theory calculations to predict the external morphology of the tetragonal GdVO4 crystal from its internal structure. The Bravais-Friedel-Donnay-Harker (BFDH) method, attachment energy (AE) method and surface energy (SE) method were used in this study. Slice energies (cohesive, attachment and specific surface) of the three main crystal faces having (110), (101) and (200) orientation and their dhkl thicknesses were computed using CRYSTAL17 code, in the frame of a 2D periodic slab model. The relative growth rate (Rhkl) and the morphological importance (MIhkl) for each unrelaxed and relaxed (hkl) face of interest were determined. Consequently, the crystal shapes predicted based upon BFDH, AE and SE methods were represented by the Wulff construction. The results of the morphology crystal predictions, based on the above methods, were compared both against each other and against the experimentally observed morphologies. A quite satisfactory agreement between the predicted and observed crystal morphologies is noticed.

Synthesis, structural elucidation, characterization and theoretical DFT study of 1-(o-tolyl)biguanidium chloride.

The structure of the new salt 1-(o-tolyl)biguanidium chloride, C9H14N5+·Cl-, has been determined by single-crystal X-ray diffraction. The salt crystallizes in the monoclinic space group C2/c. In this structure, the chloride and biguanidium hydrophilic ions are mostly connected to each other via N-H...N and N-H...Cl hydrogen bonds to form layers parallel to the ab plane around y = 1/3 and y = 2/3. The 2-methylbenzyl groups form layers between these layers around y = 0 and y = 1/2, with the methyl group forming C-H...π interactions with the aromatic ring. Intermolecular interactions on the Hirshfeld surface were investigated in terms of contact enrichment and electrostatic energy, and confirm the role of strong hydrogen bonds along with hydrophobic interactions. A correlation between electrostatic energy and contact enrichment is found only for the strongly attractive (N-H...Cl-) and repulsive contacts. Electrostatic energies between ions reveal that the interacting biguanidium cation pairs are repulsive and that the crystal is maintained by attractive cation...Cl- dimers. The vibrational absorption bands were identified by IR spectroscopy.

Crystal structure and Hirshfeld surface analysis of tris-(2,2'-bi-pyridine)-nickel(II) bis-(1,1,3,3-tetra-cyano-2-eth-oxy-propenide) dihydrate.

The title compound, [Ni(C10H8N2)3](C9H5N4O)2·2H2O, crystallizes as a racemic mixture in the monoclinic space group C2/c. In the crystal, the 1,1,3,3-tetracyano-2-ethoxypropenide anions and the water molecules are linked by O-H⋯N hydrogen bonds, forming chains running along the [010] direction. The bpy ligands of the cation are linked to the chain via C-H⋯π(cation) inter-actions involving the CH3 group. The inter-molecular inter-actions were investigated by Hirshfeld surface analysis and two-dimensional fingerprint plots.

Polarization of Electron Density Databases of Transferable Multipolar Atoms.

Polarizability is a key molecular property involved in either macroscopic (i.e., dielectric constant) and microscopic properties (i.e., interaction energies). In rigid molecules, this property only depends on the ability of the electron density (ED) to acquire electrostatic moments in response to applied electric fields. Databases of transferable electron density fragments are a cheap and efficient way to access molecular EDs. This approach is rooted in the relative conservation of the atomic ED between different molecules, termed transferability principle. The present work discusses the application of this transferability principle to the polarizability, an electron density-derived property, partitioned in atomic contributions using the Quantum Theory of Atoms In Molecules topology. The energetic consequences of accounting for in situ deformation (polarization) of database multipolar atoms are investigated in detail by using a high-quality quantum chemical benchmark.

A method to estimate statistical errors of properties derived from charge-density modelling.

Estimating uncertainties of property values derived from a charge-density model is not straightforward. A methodology, based on calculation of sample standard deviations (SSD) of properties using randomly deviating charge-density models, is proposed with the MoPro software. The parameter shifts applied in the deviating models are generated in order to respect the variance-covariance matrix issued from the least-squares refinement. This `SSD methodology' procedure can be applied to estimate uncertainties of any property related to a charge-density model obtained by least-squares fitting. This includes topological properties such as critical point coordinates, electron density, Laplacian and ellipticity at critical points and charges integrated over atomic basins. Errors on electrostatic potentials and interaction energies are also available now through this procedure. The method is exemplified with the charge density of compound (E)-5-phenylpent-1-enylboronic acid, refined at 0.45 Šresolution. The procedure is implemented in the freely available MoPro program dedicated to charge-density refinement and modelling.

Syn vs Anti Carboxylic Acids in Hybrid Peptides: Experimental and Theoretical Charge Density and Chemical Bonding Analysis.

A comparative study of syn vs anti carboxylic acids in hybrid peptides based on experimental electron density studies and theoretical calculations shows that, in the anti form, all three bond angles surrounding Ccarboxyl of the -COOH group are close to ∼120°, as expected for a C-sp2 atom, whereas in the syn form, the ∠Cα-C(O)-Ohydroxyl angle is significantly smaller by 5-10°. The oxygen atom in the carboxyl group is more electronegative in the anti form, so the polarity of the acidic O-H bond is higher in the anti form compared to the syn form, as observed within the limitations of H atom treatment in X-ray diffraction. Consequently, the investigated anti carboxylic acid forms the strongest O-H···O hydrogen bond among all model compounds. Furthermore, according to natural bond orbital analysis, the oxygen lone pairs are clearly nonequivalent, as opposed to the general notion of hybridization of equivalent sp2 and sp3 lone pairs on carbonyl or hydroxyl oxygen atoms. The hybridization of the lone pairs is directly related to the directionality and strength of hydrogen bonds.

A theoretical-electron-density databank using a model of real and virtual spherical atoms.

A database describing the electron density of common chemical groups using combinations of real and virtual spherical atoms is proposed, as an alternative to the multipolar atom modelling of the molecular charge density. Theoretical structure factors were computed from periodic density functional theory calculations on 38 crystal structures of small molecules and the charge density was subsequently refined using a density model based on real spherical atoms and additional dummy charges on the covalent bonds and on electron lone-pair sites. The electron-density parameters of real and dummy atoms present in a similar chemical environment were averaged on all the molecules studied to build a database of transferable spherical atoms. Compared with the now-popular databases of transferable multipolar parameters, the spherical charge modelling needs fewer parameters to describe the molecular electron density and can be more easily incorporated in molecular modelling software for the computation of electrostatic properties. The construction method of the database is described. In order to analyse to what extent this modelling method can be used to derive meaningful molecular properties, it has been applied to the urea molecule and to biotin/streptavidin, a protein/ligand complex.