Showing papers by "Pavel Hobza published in 2016"

Computer Modeling of Halogen Bonds and Other σ-Hole Interactions

Abstract: In the field of noncovalent interactions a new paradigm has recently become popular. It stems from the analysis of molecular electrostatic potentials and introduces a label, which has recently attracted enormous attention. The label is σ-hole, and it was first used in connection with halogens. It initiated a renaissance of interest in halogenated compounds, and later on, when found also on other groups of atoms (chalcogens, pnicogens, tetrels and aerogens), it resulted in a new direction of research of intermolecular interactions. In this review, we summarize advances from about the last 10 years in understanding those interactions related to σ-hole. We pay particular attention to theoretical and computational techniques, which play a crucial role in the field.

Benchmark Calculations of Interaction Energies in Noncovalent Complexes and Their Applications

Abstract: Data sets of benchmark interaction energies in noncovalent complexes are an important tool for quantifying the accuracy of computational methods used in this field, as well as for the development of new computational approaches. This review is intended as a guide to conscious use of these data sets. We discuss their construction and accuracy, list the data sets available in the literature, and demonstrate their application to validation and parametrization of quantum-mechanical computational methods. In practical model systems, the benchmark interaction energies are usually obtained using composite CCSD(T)/CBS schemes. To use these results as a benchmark, their accuracy should be estimated first. We analyze the errors of this methodology with respect to both the approximations involved and the basis set size. We list the most prominent data sets covering various aspects of the field, from general ones to sets focusing on specific types of interactions or systems. The benchmark data are then used to valida...

Competition between Halogen, Hydrogen and Dihydrogen Bonding in Brominated Carboranes

Abstract: Halogen bonds are a subset of noncovalent interactions with rapidly expanding applications in materials and medicinal chemistry. While halogen bonding is well known in organic compounds, it is new in the field of boron cluster chemistry. We have synthesized and crystallized carboranes containing Br atoms in two different positions, namely, bound to C- and B-vertices. The Br atoms bound to the C-vertices have been found to form halogen bonds in the crystal structures. In contrast, Br atoms bound to B-vertices formed hydrogen bonds. Quantum chemical calculations have revealed that halogen bonding in carboranes can be much stronger than in organic architectures. These findings open new possibilities for applications of carboranes, both in materials and medicinal chemistry.

A Nexus between Theory and Experiment: Non-Empirical Quantum Mechanical Computational Methodology Applied to Cucurbit[n]uril⋅Guest Binding Interactions

Abstract: A training set of eleven X-ray structures determined for biomimetic complexes between cucurbit[n]uril (CB[7 or 8]) hosts and adamantane-/diamantane ammonium/aminium guests were studied with DFT-D3 quantum mechanical computational methods to afford ΔGcalcd binding energies. A novel feature of this work is that the fidelity of the BLYP-D3/def2-TZVPP choice of DFT functional was proven by comparison with more accurate methods. For the first time, the CB[n]⋅guest complex binding energy subcomponents [for example, ΔEdispersion, ΔEelectrostatic, ΔGsolvation, binding entropy (−TΔS), and induced fit Edeformation(host), Edeformation(guest)] were calculated. Only a few weeks of computation time per complex were required by using this protocol. The deformation (stiffness) and solvation properties (with emphasis on cavity desolvation) of cucurbit[n]uril (n=5, 6, 7, 8) isolated host molecules were also explored by means of the DFT-D3 method. A high ρ2=0.84 correlation coefficient between ΔGexptl and ΔGcalcd was achieved without any scaling of the calculated terms (at 298 K). This linear dependence was utilized for ΔGcalcd predictions of new complexes. The nature of binding, including the role of high energy water molecules, was also studied. The utility of introduction of tethered [-(CH2)nNH3]+ amino loops attached to N,N-dimethyl-adamantane-1-amine and N,N,N′,N′-tetramethyl diamantane-4,9-diamine skeletons (both from an experimental and a theoretical perspective) is presented here as a promising tool for the achievement of new ultra-high binding guests to CB[7] hosts. Predictions of not yet measured equilibrium constants are presented herein.

IDD388 Polyhalogenated Derivatives as Probes for an Improved Structure-Based Selectivity of AKR1B10 Inhibitors

Abstract: Human enzyme aldo-keto reductase family member 1B10 (AKR1B10) has evolved as a tumor marker and promising antineoplastic target. It shares high structural similarity with the diabetes target enzyme aldose reductase (AR). Starting from the potent AR inhibitor IDD388, we have synthesized a series of derivatives bearing the same halophenoxyacetic acid moiety with an increasing number of bromine (Br) atoms on its aryl moiety. Next, by means of IC50 measurements, X-ray crystallography, WaterMap analysis, and advanced binding free energy calculations with a quantum-mechanical (QM) approach, we have studied their structure-activity relationship (SAR) against both enzymes. The introduction of Br substituents decreases AR inhibition potency but improves it in the case of AKR1B10. Indeed, the Br atoms in ortho position may impede these drugs to fit into the AR prototypical specificity pocket. For AKR1B10, the smaller aryl moieties of MK181 and IDD388 can bind into the external loop A subpocket. Instead, the bulkier MK184, MK319, and MK204 open an inner specificity pocket in AKR1B10 characterized by a π-π stacking interaction of their aryl moieties and Trp112 side chain in the native conformation (not possible in AR). Among the three compounds, only MK204 can make a strong halogen bond with the protein (-4.4 kcal/mol, using QM calculations), while presenting the lowest desolvation cost among all the series, translated into the most selective and inhibitory potency AKR1B10 (IC50 = 80 nM). Overall, SAR of these IDD388 polyhalogenated derivatives have unveiled several distinctive AKR1B10 features (shape, flexibility, hydration) that can be exploited to design novel types of AKR1B10 selective drugs.

New Insight into the Nature of Bonding in the Dimers of Lappert’s Stannylene and Its Ge Analogs: A Quantum Mechanical Study

Abstract: The strength and nature of the connection in Lappert’s stannylene dimer ({Sn[CH(SiMe3)2]2}2) and its smaller analogs, simplified stannylenes, as well as similar Ge complexes were studied by means of DFT-D3 calculations, energy decomposition analysis (EDA), electrostatic potential (ESP), and natural population analysis. The trans-bent structure of the investigated molecules was rationalized by means of EDA, ESP, and molecular orbital (MO) analyses. The different ESPs for the monomers studied are a result of different hybridization of the Sn (Ge) atoms. The comparably strong stabilization in the largest and the smallest systems with a dramatically different substituent size is explained by the different nature of the binding between monomers. For all complexes, it has been found that the total attractive interaction is mostly provided by the electrostatic component (>50%), followed by orbital interaction and dispersion. In the largest molecule (Lappert’s stannylene), the dispersion interaction plays a more ...

Ab initio and DFT studies of the interaction between carbonyl and thiocarbonyl groups: the role of S···O chalcogen bonds

Abstract: The chalcogen bonds formed between carbonyl bases (H2C=O and CH3- and Cl-derivatives) and carbon disulfide have been studied by density functional BLYP-D3 and ab initio CCSD(T) methods. The CCSD(T)/CBS calculated interaction energies between these molecules are moderate, ranging from −1.45 to −2.29 kcal mol−1. The charge transfer occurs from the carbonyl base to CS2 and is small. According to the AIM analysis, the molecules are bonded by S···O chalcogen bonds. In addition, weak van der Waals S···Cl and S···H interactions stabilize most of the systems. The same results can be extracted from the NBO calculations which reveal the nature of the interacting bonding and antibonding orbitals. For some of the carbonyl derivatives, other stable structures characterized by S···Cl bonds or CH···C hydrogen bonds are also predicted. A SAPT decomposition of the interaction energies allows to conclude that the electrostatic energy is the predominant component in the stronger complexes and that the dispersion energy becomes more important in the weaker van der Waals complexes.

The non-planarity of the benzene molecule in the X-ray structure of the chelated bismuth(III) heteroboroxine complex is not supported by quantum mechanical calculations

Abstract: The non-planarity of the benzene moiety in the crystal of a chelated bismuth(iii) heteroboroxine complex was not supported by DFT-D quantum chemical calculations. The observed bent structure of benzene is in fact a superimposition (thermal average) of the ensemble of thermally populated benzene structures in the complex studied.

Experimental and Theoretical Study for the Assessment of the Conformational Stability of Polymethylene-Bridged Heteroaromatic Dimers: A Case of Unprecedented Folding

Abstract: This is the first report on the folding phenomenon of pyridazinone and triazinone dimers (1–5) bridged through an alkyl chain. Among them, direct evidence of conformational preference of 1, 2, and 5 was obtained through single crystal X-ray structures. However, prevalence of folded conformations was analyzed through theoretical investigation.

Computational methods for the description of pharmacologically relevant platinum complexes – molecular structure and bond dissociation

Abstract: Cancer is after cardiovascular disease the most frequent cause of death in Europe. In 28 of 53 countries considered in this area it is already the leading cause of death and expected to gain even more importance until the year 2020. Amongst the large arsenal of different anti-cancer drugs, platinum drugs belong to the first developed anticancer drugs and still have a large impact on cancer therapy. Nevertheless therapy with platinum-anticancer drugs is accompanied by severe adverse effects caused by frequent interactions with the amino acids of different human proteins. Computational chemistry offers methods to study such interactions and even those of not yet synthesized drugs in silico. For such studies a profound knowledge of the prediction quality of various computational methods towards platinum-drug-like complexes is necessary. By this article we are aiming on delivering important accuracy information of the frequently used computational methods. Most important findings are the high performance of the double hybrid functional B2PLYP for the calculation of geometries, even in small basis sets, followed by BP86 and PBE and the still acceptable performance of the semi-empirical Method PM6-D3H4X for extremely large systems. To follow absolute energies of the dissociation process, LPNO-CEPA and B3LYP-D3 can be suggested while SCS-MP2 shows an extremely narrow standard deviation and a low maximum error, which make it an ideal candidate for relative energy calculations in the exploration of reaction mechanisms.