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Rhomboid intramembrane serine proteases have been implicated in several pathologies, and emerge as attractive pharmacological target candidates. The most potent and selective rhomboid inhibitors available to date are peptidyl α-ketoamides, but their selectivity for diverse rhomboid proteases and strategies to modulate it in relevant contexts are poorly understood. This gap, together with the lack of suitable in vitro models, hinders ketoamide development for relevant eukaryotic rhomboid enzymes. Here we explore the structure-activity relationship principles of rhomboid inhibiting ketoamides by medicinal chemistry and enzymatic in vitro and in-cell assays with recombinant rhomboid proteases GlpG, human mitochondrial rhomboid PARL and human RHBDL2. We use X-ray crystallography in lipidic cubic phase to understand the binding mode of one of the best ketoamide inhibitors synthesized here containing a branched terminal substituent bound to GlpG. In addition, to extend the interpretation of the co-crystal structure, we use quantum mechanical calculations and quantify the relative importance of interactions along the inhibitor molecule. These combined experimental analyses implicates that more extensive exploration of chemical space at the prime side is unexpectedly powerful for the selectivity of rhomboid inhibiting ketoamides. Together with variations in the peptide sequence at the non-prime side, or its non-peptidic alternatives, this strategy enables targeted tailoring of potent and selective ketoamides towards diverse rhomboid proteases including disease-relevant ones such as PARL and RHBDL2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Six-vertex closo-SB 5 Cl 5 (1) and ten-vertex closo-1-SB 9 Cl 9 (2) thiaboranes have been prepared, besides the already known 12-vertex closo-SB 11 Cl 11 (3), from the co-pyrolysis reaction of B 2 Cl 4 with S 2 Cl 2 at 280 °C in vacuo. The compounds are sublimable, off-white solids. Their elemental composition has been determined by high-resolution mass spectrometry. They were further characterized by one- and two-dimensional 11 B NMR spectroscopy and X-ray structure determination for 1 and 3. Ab initio/GIAO/NMR computations support octahedral, bicapped square-antiprismatic, and icosahedral geometries for 1, 2 and 3, respectively, as expected based on their closo-electron counts. 1 is the first isolated example of a neutral polyhedral closo-thiaborane with a cluster size smaller than ten vertices. The solid-state structure of 3 is one of the rare examples of a single-crystal X-ray structure determination of an icosahedral heteroborane reported. The corresponding crystal-packing forces show the different role of chalcogen bonding in these octahedral and icosahedral crystals. In addition, there is a mass-spectrometry evidence for the recurrent formation of further thiaborane homologs of closo-SB n Cl n with n=4, 6, 10, and supra-icosahedral 12., (© 2024 Wiley-VCH GmbH.)

Schistosomiasis, caused by a parasitic blood fluke of the genus Schistosoma, is a global health problem for which new chemotherapeutic options are needed. We explored the scaffold of gallinamide A, a natural peptidic metabolite of marine cyanobacteria that has previously been shown to inhibit cathepsin L-type proteases. We screened a library of 19 synthetic gallinamide A analogs and identified nanomolar inhibitors of the cathepsin B-type protease SmCB1, which is a drug target for the treatment of schistosomiasis mansoni. Against cultured S. mansoni schistosomula and adult worms, many of the gallinamides generated a range of deleterious phenotypic responses. Imaging with a fluorescent-activity-based probe derived from gallinamide A demonstrated that SmCB1 is the primary target for gallinamides in the parasite. Furthermore, we solved the high-resolution crystal structures of SmCB1 in complex with gallinamide A and its two analogs and describe the acrylamide covalent warhead and binding mode in the active site. Quantum chemical calculations evaluated the contribution of individual positions in the peptidomimetic scaffold to the inhibition of the target and demonstrated the importance of the P1' and P2 positions. Our study introduces gallinamides as a powerful chemotype that can be exploited for the development of novel antischistosomal chemotherapeutics.

Accurate estimation of protein-ligand binding affinity is the cornerstone of computer-aided drug design. We present a universal physics-based scoring function, named SQM2.20, addressing key terms of binding free energy using semiempirical quantum-mechanical computational methods. SQM2.20 incorporates the latest methodological advances while remaining computationally efficient even for systems with thousands of atoms. To validate it rigorously, we have compiled and made available the PL-REX benchmark dataset consisting of high-resolution crystal structures and reliable experimental affinities for ten diverse protein targets. Comparative assessments demonstrate that SQM2.20 outperforms other scoring methods and reaches a level of accuracy similar to much more expensive DFT calculations. In the PL-REX dataset, it achieves excellent correlation with experimental data (average R 2  = 0.69) and exhibits consistent performance across all targets. In contrast to DFT, SQM2.20 provides affinity predictions in minutes, making it suitable for practical applications in hit identification or lead optimization., (© 2024. The Author(s).)

The recent success in the formation of chlorinated telluraboranes and the reactivities of pnictogenaboranes prompted us to re-examine the vacuum co-pyrolysis of B 2 Cl 4 with Se 2 Cl 2 at various molar ratios and temperatures in order to search for the generation of other polyhedral selenaboranes than closo -SeB 5 Cl 5 (1a) and closo -SeB 11 Cl 11 (1b), the latter being observed earlier. Interestingly, a new compound with the elemental composition SeB 9 Cl 9 (2) was detected, this time by high- and low-resolution mass spectrometry. Further characterization by 1- and 2-D 11 B-NMR spectroscopy suggests that 2 should adopt a closed bicapped square-antiprismatic geometry with selenium at the apical position. Moreover, vacuum sublimation gave suitable crystals of 1b, which were subjected to single-crystal X-ray structure determination. Crystallographic data analysis confirmed that 1b, consistent with its 26 skeletal electron count, adopts a distorted icosahedral structure close to the symmetry of C 5v . Computations at the DFT-D3 level have revealed that 33% of the total computed binding motifs in the grown 1b crystals are due to the very strong chalcogen bonding. Moreover, SAPT decomposition has shown that the bonding motifs in the crystals are stabilized mainly by dispersion and electrostatic terms. Homodecoupling and high resolution 11 B NMR and 77 Se NMR experiments have resolved both coupling constants 1 J ( 11 B 11 B) and 1 J ( 77 Se 11 B) as well as the 77 Se chemical shift of 1a and 1b, which are in reasonable agreement with the corresponding computed values. The computed 11 B chemical shifts of 2 were determined by the well-established DFT/GIAO/NMR structural tool based on its B3LYP/6-311+G** internal coordinates. They agree well with the experimental values and provide a good representation of the molecular structure of 2 in solution. The extraordinary downfield 11 B NMR chemical shift of B(10) in 2 has been ascribed to the intensive paramagnetic contribution to the shielding tensor in this bicapped square-antiprismatic motif. Calculations of the synproportionation free energies of smaller ( n - 1) closo -selenaboranes with larger-sized ( n + 1) ones support the extraordinary stability of octahedral, bicapped square-antiprismatic and icosahedral closo motifs in the SeB n Cl n family ( n = 4-12).

Borane and heteroborane clusters have been known as neutral or anionic species. In contrast to them, several ten-vertex monocationic nido and closo dicarbaborane-based systems have recently emerged from the reaction of the parent bicapped-square antiprismatic dicarbaboranes with N-heterocyclic carbenes followed by the protonization of the corresponding nido intermediates. The expansion of these efforts has afforded the very first closo -dicationic octahedral phosphahexaborane along with new closo- monocationic pnictogenahexaboranes of the same shapes. All are the products of the one-pot procedure that consists in the reaction of the same carbenes with the parent closo -1,2-Pn 2 B 4 Br 4 (Pn = As, P). Whereas in the case of phosphorus such a monocation appears to be a mixture of stable intermediates, and arsenahexaboranyl monocation has occurred as the final product, all of them without using any subsequent reaction. The well-established DFT/ZORA/NMR approach has unambiguously confirmed the existence of these species in solution, and computed electrostatic potentials have revealed the delocalization of the positive charge in these monocations and in the very first dication, namely within the octahedral shapes in both cases., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Six-vertex closo-TeB 5 Cl 5 (1) and twelve-vertex closo-TeB 11 Cl 11 (2) telluraboranes have been prepared via co-pyrolysis of B 2 Cl 4 with TeCl 4 in vacuo at temperatures between 360 °C and 400 °C. Both compounds are sublimable, off-white solids, and they have been characterized by one- and two-dimensional 11 B NMR and high-resolution mass spectroscopy. Both ab initio/GIAO/NMR and DFT/ZORA/NMR computations support octahedral and icosahedral geometries for 1 and 2, respectively, as expected due to their closo-electron counts. The octahedral structure of 1 has been confirmed by single-crystal X-ray diffraction on an incommensurately modulated crystal. The corresponding bonding properties have been analyzed in terms of the intrinsic bond orbital (IBO) approach. 1 is the first example of a polyhedral telluraborane with a cluster size smaller than 10 vertices., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

In this theoretical study, we set out to demonstrate the substitution effect of PEDOT analogues on planarity as an intrinsic indicator for electronic performance. We perform a quantum mechanical (DFT) study of PEDOT and analogous model systems and demonstrate the usefulness of the ωB97X-V functional to simulate chalcogen bonds and other noncovalent interactions. We confirm that the chalcogen bond stabilizes the planar conformation and further visualize its presence via the electrostatic potential surface. In comparison to the prevalent B3LYP, we gain 4-fold savings in computational time and simulate model systems of up to a dodecamer. Implications for design of conductive polymers can be drawn from the results, and an example for self-doped polymers is presented where modulation of the strength of the chalcogen bond plays a significant role.

Modern computational protocols based on the density functional theory (DFT) infer that polyhedral closo ten-vertex carboranes are key starting stationary states in obtaining ten-vertex cationic carboranes. The rearrangement of the bicapped square polyhedra into decaborane-like shapes with open hexagons in boat conformations is caused by attacks of N-heterocyclic carbenes (NHCs) on the closo motifs. Single-point computations on the stationary points found during computational examinations of the reaction pathways have clearly shown that taking the "experimental" NHCs into account requires the use of dispersion correction. Further examination has revealed that for the purposes of the description of reaction pathways in their entirety, i.e., together with all transition states and intermediates, a simplified model of NHCs is sufficient. Many of such transition states resemble in their shapes those that dictate Z -rearrangement among various isomers of closo ten-vertex carboranes. Computational results are in very good agreement with the experimental findings obtained earlier.

Among non-covalent interactions, B-H⋯π and C-H⋯π hydrogen bonding is rather weak and less studied. Nevertheless, since both can affect the energetics of protein-ligand binding, their understanding is an important prerequisite for reliable predictions of affinities. Through a combination of high-resolution X-ray crystallography and quantum-chemical calculations on carbonic anhydrase II/carborane-based inhibitor systems, this paper provides the first example of B-H⋯π hydrogen bonding in a protein-ligand complex. It shows that the B-H⋯π interaction is stabilized by dispersion, followed by electrostatics. Furthermore, it demonstrates that the similar C-H⋯π interaction is twice as strong, with a slightly smaller contribution of dispersion and a slightly higher contribution of electrostatics. Such a detailed insight will facilitate the rational design of future protein ligands, controlling these types of non-covalent interactions.

Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile Gü1303 and a 3-cyano-3-aza-β-amino acid Gü2602 . Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of Gü2602 is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs.

Reactions of the perhalogenated polyhedral pnictogenaboranes closo -1,2-Pn 2 B 4 Hal 4 (Pn = P, As; Hal = Cl, Br) with Lewis bases are presently being studied with a focus on rationalizing the sites of nucleophilic attacks on clusters bearing σ-holes. These σ-holes are localized both on pnictogens and, for Hal = Br, on bromine atoms, as revealed by electrostatic potential (ESP) and intrinsic bond orbital (IBO) analyses. Surprisingly, the attack of the cyclic ether THF on closo -1,2-Pn 2 B 4 Br 4 does not occur on the site with the largest positive partial charge, centered in the middle of the pnictogen-pnictogen vector. Instead, presumably promoted by the positivated bromine substituents, THF inserts into the boron-bromine bonds of the negatively charged boron atoms opposite to the pnictogen atoms to form 4-(4-bromobut-1-oxy)- closo -1,2-Pn 2 B 4 Br 3 ( 1-PB and 1-AsB ) and 4,6-(4-bromobut-1-oxy) 2 - closo -1,2-Pn 2 B 4 Br 2 ( 2-PB and 2-AsB ). 11 B and 31 P chemical shift computations at various levels support the assignments of the signals, which reflect the correctness of the molecular geometries in solutions. The Lewis-acidic perchlorinated analogues closo- 1,2-P 2 B 4 Cl 4 , closo -1,2-As 2 B 4 Cl 4 , and the mixed closo- 1,2-AsPB 4 Cl 4 bear negative charges. These negative charges are revealed by the V s,max values when computing the electrostatic potentials both on the boron and the chlorine atoms. Due to this negative charge, the analogues do not react with THF unless they are heated above 66 °C, where they slowly decompose to borate esters B(OR) 3 without the formation of concrete intermediates. The evaluation of 31 P NMR data of 1-PB has allowed the experimental determination of the coupling constant 1 J ( 31 P(1), 31 P(2)) = |143| Hz in a closo -diphosphaborane for the first time, which agrees well with the computed value of -178 Hz. The pioneering joint experimental vs computational interpretation of 31 P NMR spectra in the area of boron cluster chemistry was decisive for the structural characterization of 1-PB and 2-PB .

Reported herein are mutual rearrangements in the whole series of seven bicapped-square antiprismatic closo -C 2 B 8 H 10 by means of high-quality computations that disprove the earlier postulated dsd (diamond-square-diamond) scheme for these isomerizations. The experimentally existing closo -1,2-C 2 B 8 H 10 was able to be converted to 1,6-, and 1,10-isomers by pyrolysis, and the dsd (diamond-square-diamond) mechanism was offered as an explanation of these processes. However, these computations disprove the postulated dsd scheme for these isomerizations that take place in the ten-vertex closo series. Experimentally observed thermal rearrangements, both in the parent and substituted closo -1,2-C 2 B 8 H 10 , closo -1-CB 9 H 10 - , and closo -B 10 H 10 2- , indirectly support these refined computations. All these processes are based on the new concept of the so-called Z -mechanism, being consistent with a transition state of a boat shape with an open hexagonal belt that results from the initial breakage of three bonds. Such bond breakings and the consequent bond formations bring to mind the shape of the letter Z . In effect, the pattern of multicenter bonding shifts from reactant through a transition state to product. The molecular rearrangements that are available experimentally favour either the axial or equatorial isomers, and this ratio depends on temperature and the type of cluster and its substitution.

Polyhedral boranes and heteroboranes appear almost exclusively as neutral or anionic species, while the cationic ones are protonated at exoskeletal heteroatoms or they are instable. Here we report the reactivity of 10-vertex closo-dicarbadecaboranes with one or two equivalents of N-heterocyclic carbene to 10-vertex nido mono- and/or bis-carbene adducts, respectively. These complexes easily undergo a reaction with HCl to give cages of stable and water soluble 10-vertex nido-type cations with protonation in the form of a BHB bridge or 10-vertex closo-type cations containing one carbene ligand when originating from closo-1,10-dicarbadecaborane. The reaction of a 10-vertex nido mono-carbene adduct with phosphorus trichloride gives nido-11-vertex 2-phospha-7,8-dicarbaundecaborane, which undergoes an oxidation of the phosphorus atom to P = O, while the product of a bis-carbene adduct reaction is best described as a distorted C 2 B 6 H 8 fragment bridged by the (BH) 2 PCl 2 + moiety., (© 2021. The Author(s).)

In this study, we have focused on the structure-based design of the inhibitors of one of the two SARS-CoV-2 methyltransferases (MTases), nsp14. This MTase catalyzes the transfer of the methyl group from S -adenosyl-l-methionine (SAM) to cap the guanosine triphosphate moiety of the newly synthesized viral RNA, yielding the methylated capped RNA and S -adenosyl-l-homocysteine (SAH). As the crystal structure of SARS-CoV-2 nsp14 is unknown, we have taken advantage of its high homology to SARS-CoV nsp14 and prepared its homology model, which has allowed us to identify novel SAH derivatives modified at the adenine nucleobase as inhibitors of this important viral target. We have synthesized and tested the designed compounds in vitro and shown that these derivatives exert unprecedented inhibitory activity against this crucial enzyme. The docking studies nicely explain the contribution of an aromatic part attached by a linker to the position 7 of the 7-deaza analogues of SAH.

The electrophilic substitution of icosahedral closo- 1-SB 11 H 11 with methyl iodide has resulted in two B-functionalized thiaboranes, 7,12-I 2 -2,3,4,5,6,8,9,10,11-(CH 3 ) 9 -1- closo -SB 11 and 7,8,12-I 3 -2,3,4,5,6,9,10,11-(CH 3 ) 8 - closo -1-SB 11 , with the former being significantly predominant. These two icosahedral thiaboranes are the first cases of polysubstituted polyhedral boron clusters with another vertex that differs from B and C. Such polyfunctionalizations have increased the earlier observed thiaborane icosahedral barrier, not exhibiting any reactivity toward bases, unlike the parent thiaborane. The search for methylation pathways has revealed that the complete B 11 -methylation is impossible, like in the case of decaborane(14), where this seems to be a result of the positively charged upper parts of these two molecules.

Schistosomiasis, a parasitic disease caused by blood flukes of the genus Schistosoma , is a global health problem with over 200 million people infected. Treatment relies on just one drug, and new chemotherapies are needed. Schistosoma mansoni cathepsin B1 (SmCB1) is a critical peptidase for the digestion of host blood proteins and a validated drug target. We screened a library of peptidomimetic vinyl sulfones against SmCB1 and identified the most potent SmCB1 inhibitors reported to date that are active in the subnanomolar range with second order rate constants ( k 2nd ) of ∼2 × 10 5 M -1 s -1 . High resolution crystal structures of the two best inhibitors in complex with SmCB1 were determined. Quantum chemical calculations of their respective binding modes identified critical hot spot interactions in the S1' and S2 subsites. The most potent inhibitor targets the S1' subsite with an N -hydroxysulfonic amide moiety and displays favorable functional properties, including bioactivity against the pathogen, selectivity for SmCB1 over human cathepsin B, and reasonable metabolic stability. Our results provide structural insights for the rational design of next-generation SmCB1 inhibitors as potential drugs to treat schistosomiasis.

Influenza A virus (IAV) encodes a polymerase composed of three subunits: PA, with endonuclease activity, PB1 with polymerase activity and PB2 with host RNA five-prime cap binding site. Their cooperation and stepwise activation include a process called cap-snatching, which is a crucial step in the IAV life cycle. Reproduction of IAV can be blocked by disrupting the interaction between the PB2 domain and the five-prime cap. An inhibitor of this interaction called pimodivir (VX-787) recently entered the third phase of clinical trial; however, several mutations in PB2 that cause resistance to pimodivir were observed. First major mutation, F404Y, causing resistance was identified during preclinical testing, next the mutation M431I was identified in patients during the second phase of clinical trials. The mutation H357N was identified during testing of IAV strains at Centers for Disease Control and Prevention. We set out to provide a structural and thermodynamic analysis of the interactions between cap-binding domain of PB2 wild-type and PB2 variants bearing these mutations and pimodivir. Here we present four crystal structures of PB2-WT, PB2-F404Y, PB2-M431I and PB2-H357N in complex with pimodivir. We have thermodynamically analysed all PB2 variants and proposed the effect of these mutations on thermodynamic parameters of these interactions and pimodivir resistance development. These data will contribute to understanding the effect of these missense mutations to the resistance development and help to design next generation inhibitors.

Azapeptide nitriles are postulated to reversibly covalently react with the active-site cysteine residue of cysteine proteases and form isothiosemicarbazide adducts. We investigated the interaction of azadipeptide nitriles with the cathepsin B1 drug target (SmCB1) from Schistosoma mansoni , a pathogen that causes the global neglected disease schistosomiasis. Azadipeptide nitriles were superior inhibitors of SmCB1 over their parent carba analogs. We determined the crystal structure of SmCB1 in complex with an azadipeptide nitrile and analyzed the reaction mechanism using quantum chemical calculations. The data demonstrate that azadipeptide nitriles, in contrast to their carba counterparts, undergo a change from E - to Z -configuration upon binding, which gives rise to a highly favorable energy profile of noncovalent and covalent complex formation. Finally, azadipeptide nitriles were considerably more lethal than their carba analogs against the schistosome pathogen in culture, supporting the further development of this chemotype as a treatment for schistosomiasis.

The biological effects of flavonoids on mammal cells are diverse, ranging from scavenging free radicals and anti-cancer activity to anti-influenza activity. Despite appreciable effort to understand the anti-influenza activity of flavonoids, there is no clear consensus about their precise mode-of-action at a cellular level. Here, we report the development and validation of a screening assay based on AlphaScreen technology and illustrate its application for determination of the inhibitory potency of a large set of polyols against PA N-terminal domain (PA-Nter) of influenza RNA-dependent RNA polymerase featuring endonuclease activity. The most potent inhibitors we identified were luteolin with an IC 50 of 72 ± 2 nM and its 8-C-glucoside orientin with an IC 50 of 43 ± 2 nM. Submicromolar inhibitors were also evaluated by an in vitro endonuclease activity assay using single-stranded DNA, and the results were in full agreement with data from the competitive AlphaScreen assay. Using X-ray crystallography, we analyzed structures of the PA-Nter in complex with luteolin at 2.0 Å resolution and quambalarine B at 2.5 Å resolution, which clearly revealed the binding pose of these polyols coordinated to two manganese ions in the endonuclease active site. Using two distinct assays along with the structural work, we have presumably identified and characterized the molecular mode-of-action of flavonoids in influenza-infected cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interest or personal relationship that could have appeared to influence the work reported in the paper., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

The success of approximate computational methods, such as molecular mechanics, or dispersion-corrected density functional theory, in the description of non-covalent interactions relies on accurate parameterizations. Benchmark data sets are thus required. This area is well developed for organic molecules and biomolecules but practically non-existent for boron clusters, which have been gaining in importance in modern drug as well as material design. To fill this gap, we have introduced two data sets featuring the most common non-covalent interaction of boron clusters, the dihydrogen bond, and calculated reference interaction energies at the "golden standard" CCSD(T)/CBS level. The boron clusters studied interact with formamide, methanol, water and methane at various distances and in two geometrical arrangements. The performance of the tested approximate methods is variable and recommendations for further use are given., (© 2020 Wiley-VCH GmbH.)

9-Br-closo-1,2-C 2 B 10 H 11 has been prepared and its gas-phase structure has been examined by means of gas electron diffraction. The structure of the carbaborane core is similar to the structure of the parent compound, which is of C 2v symmetry. A DFT-based search for the corresponding reaction pathway of the bromination of closo-1,2-C 2 B 10 H 12 revealed that the catalytic amount of aluminum reduces the barrier of the initial attack of the bromination agent toward the negatively charged part of the icosahedral carbaborane, i. e., the first transition state, from about 40 to about 27 kcalmol -1 . The Br-Br bond is weakened by an intermediate binding to the large π-hole on the aluminum atom of AlBr 3 , which is the driving force for the AlBr 3 -catalyzed bromination., (© 2020 The Authors. ChemPlusChem published by Wiley-VCH GmbH.)

Quantum mechanical (QM) methods have been gaining importance in structure-based drug design where a reliable description of protein-ligand interactions is of utmost significance. However, strategies i. e. QM/MM, fragmentation or semiempirical (SQM) methods had to be pursued to overcome the unfavorable scaling of QM methods. Various SQM-based approaches have significantly contributed to the accuracy of docking and improvement of lead compounds. Parametrizations of SQM and implicit solvent methods in our laboratory have been instrumental to obtain a reliable SQM-based scoring function. The experience gained in its application for activity ranking of ligands binding to tens of protein targets resulted in setting up a faster SQM/COSMO scoring approach, which outperforms standard scoring methods in native pose identification for two dozen protein targets with ten thousand poses. Recently, SQM/COSMO was effectively applied in a proof-of-concept study of enrichment in virtual screening. Due to its superior performance, feasibility and chemical generality, we propose the SQM/COSMO approach as an efficient tool in structure-based drug design., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The paper reports specific syntheses of methylated decaborane(14), nido -B 10 H 14 ( 1 ), derivatives. The reaction of 1 with an excess of neat MeI and AlCl 3 yields 1,2,3,4-Me 4 - nido -B 10 H 10 ( 2 ) essentially quantitatively when performed at room temperature. Heating the same mixture to 120 °C provides 1-I-2,3,4,5,7,8,10-Me 7 - nido -B 10 H 6 ( 3a ). The formation of analogous 1-CF 3 SO 2 O-2,3,4,5,7,8,10-Me 7 - nido -B 10 H 6 ( 3b ) is achieved by heating 1 or 2 with an excess of MeSO 3 CF 3 in the presence of a catalytic amount of HOSO 2 CF 3 to 120 °C. Compounds 2 and 3 can be deprotonated to yield the corresponding anions [1,2,3,4-Me 4 - nido -B 10 H 9 ] - ( 2 - ), [1-I-2,3,4,5,7,8,10-Me 7 - nido -B 10 H 5 ] - ( 3a - ), and [1-CF 3 SO 2 O-2,3,4,5,7,8,10-Me 7 - nido -B 10 H 5 ] - ( 3b - ). The structure of all the compounds isolated has been unambiguously confirmed by multinuclear ( 11 B and 1 H) NMR measurements, and the structures of 2 - , 3a , 3a - , and 3b have been established by X-ray diffraction analyses. The very high volatility of 2 has made it impossible to apply X-ray diffraction in this case; therefore, its structure has been derived computationally using the ab initio/GIAO/NMR tool. DFT-based computational protocols have also outlined the reason why it is impossible to obtain an octamethyl derivative of 1 experimentally.

We report on the discovery of norbornyl moiety as a novel structural motif for cyclin-dependent kinase 2 (CDK2) inhibitors which was identified by screening a carbocyclic nucleoside analogue library. Three micromolar hits were expanded by the use of medicinal chemistry methods into a series of 16 novel compounds. They had prevailingly micromolar activities against CDK2 and the best compound of the series attained IC 50 of 190 nM. The binding modes were explored in molecular details by modeling and docking. Quantum mechanics-based scoring was used to rationalize the affinities. In conclusion, the discovered 9-hydroxymethylnorbornyl moiety was shown by joint experimental-theoretical efforts to be able to serve as a novel substituent for CDK2 inhibitors. This finding opens door to the exploration of chemical space towards more effective derivatives targeting this important class of protein kinases., (© 2020 John Wiley & Sons Ltd.)

The supramolecular recognition of closo,closo-[B 21 H 18 ] - by cyclodextrins (CDs) has been studied in aqueous solution by isothermal titration calorimetry and nuclear magnetic resonance spectroscopy. These solution studies follow up on previous mass-spectrometric measurements and computations, which indicated the formation and stability of CD ⋅ B 21 H 18 - complexes in the gas phase. The thermodynamic signature of solution-phase binding is exceptional, the association constant for the γ-CD complex with B 21 H 18 - reaches 1.8×10 6  M -1 , which is on the same order of magnitude as the so far highest observed value for the complex between γ-CD and a metallacarborane. The nature of the intermolecular interaction is also examined by quantum-mechanical computational protocols. These suggest that the desolvation penalty, which is particularly low for the B 21 H 18 - anion, is the decisive factor for its high binding strength. The results further suggest that the elliptical macropolyhedral boron hydride is another example of a CD binder, whose extraordinary binding affinity is driven by the chaotropic effect, which describes the intrinsic affinity of large polarizable and weakly solvated chaotropic anions to hydrophobic cavities and surfaces in aqueous solution., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Rationale: For the risk assessment of penconazole in the environment and the evaluation of the possible consequences of its use, it is important to determine how its reactivity and degradation are influenced by metals commonly found in nature, such as copper and zinc., Methods: Changes in the reactivity of penconazole in the presence of zinc/copper ions were studied using electrospray ionisation mass spectrometry and density functional theory calculations., Results: Many penconazole complexes with copper and zinc ions were created; a comparison of the elements showed that a few complexes were formed analogously (doubly charged complexes with four penconazole molecules, singly charged complexes with chlorine as a counterion and singly charged complexes with deprotonated penconazole as a counterion). The metal complexes with different structures indicated different reactivity of penconazole with copper and zinc., Conclusions: The experimental and computational approaches have revealed different changes in the structure of penconazole. In the Zn(II) complex, penconazole deprotonated to stabilise the bond to Zn(II). In the Cu(II) complex, it loses one chlorine atom, creates an additional ring between the triazole ring and the phenyl ring, and/or creates a double bond in the short aliphatic chain., (© 2019 John Wiley & Sons, Ltd.)

Although 1-Ph - 2-X- closo -1,2-C 2 B 10 H 10 (X = F, Cl, Br, I) derivatives had been computed to have positive values of the heat of formation, it was possible to prepare them. The corresponding solid-state structures were computationally analyzed. Electrostatic potential computations indicated the presence of highly positive σ-holes in the case of heavy halogens. Surprisingly, the halogen•••π interaction formed by the Br atom was found to be more favorable than that of I., Competing Interests: The authors declare no conflict of interest.

Human cathepsin D (CatD), a pepsin-family aspartic protease, plays an important role in tumor progression and metastasis. Here, we report the development of biomimetic inhibitors of CatD as novel tools for regulation of this therapeutic target. We designed a macrocyclic scaffold to mimic the spatial conformation of the minimal pseudo-dipeptide binding motif of pepstatin A, a microbial oligopeptide inhibitor, in the CatD active site. A library of more than 30 macrocyclic peptidomimetic inhibitors was employed for scaffold optimization, mapping of subsite interactions, and profiling of inhibitor selectivity. Furthermore, we solved high-resolution crystal structures of three macrocyclic inhibitors with low nanomolar or subnanomolar potency in complex with CatD and determined their binding mode using quantum chemical calculations. The study provides a new structural template and functional profile that can be exploited for design of potential chemotherapeutics that specifically inhibit CatD and related aspartic proteases.

Chalcogen atoms are a class of substituents capable of generating inner and outer derivatives of boron clusters. It is well known that chalcogenated boron clusters can form strong σ-hole interactions when a chalcogen atom is a part of an icosahedron. This paper studies σ-hole interactions of dicarbaboranes with two exopolyhedral chalcogen atoms bonded to carbon vertices. Specifically, a computational investigation has been carried out on the co-crystal of (1,2-C 2 B 10 H 10 ) 2 Se 4 •toluene and a single crystal of (1,2-C 2 B 10 H 10 ) 2 Te 4 .

The concept of icosahedral barrier has been expanded from the chemistry of carbaboranes to the area of thiaboranes. Both representatives of this barrier, i. e., closo-1,2-C 2 B 10 H 12 and closo-1-SB 11 H 11 , are similar in their electron distribution, which is dominated by positive charge in the midpoint of the C-C vector and on the sulfur atom with experimentally determined dipole moments of 4.50 D and 3.64 D, respectively. This is a driving force for their reactivity as exemplified by their reactions with different carbon functionalities. Icosahedral closo-1-SB 11 H 11 reacts both with an electron sextet containing carbon (in the form of N-heterocyclic carbenes), reported earlier, and with methyl iodide with an electron octet on the carbon. The latter reaction provides hexamethylated thiaborane on the basis of methylation so far unknown in this area of heteroborane chemistry. The computations of the heat of formation (ΔH f 298 ) make it possible to estimate the height of the barrier as well as to propose closo-thiaboranes beyond the barrier. Eleven and twelve vertex thiaboranes with nido electron count are known experimentally for breaking the barrier. These computations also suggest that the larger nido-thiaboranes are promising candidates for the corresponding experimental availability, i. e., the ΔH f 298 of a 13-vertex nido-thiaborane cluster has been computed to be more negative than that of the well-known nido-SB 10 H 11 - cluster (-6.7 and -5.6 kcal mol -1 per vertex, respectively)., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Decaborane(14), nido-B 10 H 14 , is the major commercially available molecular building block in boron cluster chemistry. The condensation of two such {nido-B 10 } blocks gives the known isomers of B 18 H 22 - a molecule used in the fabrication of p-type semiconductors and capable of blue laser emission. Here, we computationally determine the structures and thermodynamic stabilities of 20 possible B 26 H 30 regioisomers constructed from the fusion of three {nido-B 10 } blocks with the three subclusters conjoined by two-boron atom shared edges. In addition, density functional theory, time-dependent (TD)-DFT and multiconfigurational CASPT2 methods have been used to model and investigate the physical and photophysical properties of the three most stable of these isomers. Our findings predict these isomers to be potentially useful materials for the semiconductor industry, as high boron-content doping agents, and in the fabrication of new optical materials.

Superconductivity in polycrystalline and thin-film MgB2 is strongly affected by the termination of its surface, but a reliable determination of the surface termination is still a challenging task of surface chemistry. Here, the surface properties of superconducting MgB2 were investigated using a combination of inverse gas chromatography and van der Waals corrected density functional theory calculations. The dispersive surface energy was measured as a function of the surface coverage and its value (58 mJ m-2 to 48 mJ m-2) was verified by high-level non-local EXX + RPA calculations, which predicted that the dispersive contribution to the cleavage energy was 56 mJ m-2. The isosteric adsorption enthalpies of cyclohexane, dioxane, acetone and acetonitrile molecules were measured on an MgB2 sample and compared to the DFT calculated enthalpies for the Mg-terminated MgB2, B-terminated MgB2 and MgO(001) surfaces. The close agreement between theory and experiment for the Mg-terminated surface suggested that the magnesium termination is the dominant surface phase of MgB2. Thus, combining inverse gas chromatography experiments with theoretical calculations may provide information about the surface termination.

The thiaboranes closo-1-SB11H11 (1a) and 12-I-closo-1-SB11H10 (1b) react with 4-(dimethylamino)pyridine under inert conditions upon the formation of the nido-type thiaboranes 9-B{(4-Me2N)C5NH4}2(H)-7-SB10H11 and 9-B{(4-Me2N)C5NH4}2(H)-5-I-7-SB10H10 containing an exoskeletal B-H group. The same type of B-H moiety is also stabilised by one bipyridine molecule in a chelating fashion. These complexes are unstable in solution, and in air and hydrolyse to monodeboronated ionic compounds having [nido-7-SB10H11]- or [5-I-nido-7-SB10H10]- anions which are also products of the reactions of 1a and 1b with other N-bases such as pyridine, ammonia and DABCO. The extrusion of one boron and one sulphur atom takes place when 1a reacts with 2,6-di-tert-butylpyridine to yield decaborane.

Methyl-camouflaged dicarbaboranes closo-1,2- and 1,10-H 2 C 2 B 8 Me 8 have been prepared in high yields either from nido-5,6-H 2 C 2 B 8 H 10 or closo-1,2-H 2 C 2 B 8 H 8 via electrophilic methylation reactions and cluster-rearrangement methods. Prepared were also monosubstituted derivatives of general formulation closo-H 2 C 2 B 8 Me 7 -X (X = I or OTf). The permethylated compounds exhibit extreme air stability in comparison to unprotected counterparts as a consequence of rigid, egg-shaped hydrocarbon structures incorporating inner C 2 B 8 carborane scaffolding. The structures of all compounds isolated were confirmed unambiguously by multinuclear ( 11 B, 1 H, 13 C, and 19 F) NMR measurements, supported by X-ray diffraction analyses and geometry optimization methods on several compounds.

The 12-X- closo-SB 11 H 10 (X = H or I) thiaboranes react with one or two molar equivalents of various N-heterocyclic carbenes (NHCs) to give the deprotonated 12-vertex species of [12-X-SB 11 H 9 ·NHC] - [NHC-H] + composition as kinetic products. The use of one molar equivalent of a sterically more hindered NHC reactant leads to the formation of 12-X-SB 11 H 10 ·NHC adducts with a heavily distorted cage and the nido electron count. Further reaction of 12-I-SB 11 H 10 ·NHC to deboronated 12-X-SB 10 H 9 ·NHC proceeds in acetone to complete the closo- nido reaction pathway under the thermodynamic control. The structures of all compounds have been investigated by NMR spectroscopy and diffraction techniques. The results are supported by theoretical methods.

Carbaboranes 1,2-(EH) 2 -closo-1,2-C 2 B 10 H 10 (E=S, Se) were prepared, in the case of E=Se for the first time. Their semi-experimental equilibrium molecular structures were established by the concerted use of quantum-chemical calculations and gas electron diffraction. A method was developed and implemented to quantify the contribution of experimental data to each refined structural parameter. The accuracy of the experimental structures and those calculated at the MP2 level of theory were gauged by comparison of experimental 11 B NMR chemical shifts with quantum-chemically computed values; the inclusion of electron correlation (GIAO-MP2) provided superior results. For the purpose of geometrical prediction, the remaining group 16 elements were considered, and the icosahedral structures for E=O and Te were also computed; for E=O the same theoretical approach was used as for E=S, and for E=Te a description similar to that for E=Se was employed., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Electrophilic methylation of the closo -1,10-R 2 C 2 B 8 H 8 (1) (R = H or Me) dicarbaboranes at higher temperatures or thermal rearrangement of the 1,6-R 2 C 2 B 8 Me 8 (3) compounds at 400-500 °C generated the B-permethylated derivatives closo -1,10-R 2 C 2 B 8 Me 8 (2) in quantitative (>95%) yields. The compounds exhibit extreme air stability as a consequence of a rigid, egg shaped hydrocarbon structures incorporating inner 1,10-C 2 B 8 carborane core., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A chalcogen bond is a nonclassical noncovalent interaction which can stabilise small-molecule crystals as well as protein structures. Here, we systematically explore the stabilising potential of chalcogen bonding in protein-ligand complexes in the Protein Data Bank (PDB). We have found that a large fraction (23 %) of complexes with a S/Se-containing ligand feature close S/Se⋅⋅⋅O/N/S contacts. Eleven non-redundant representative potential S/Se⋅⋅⋅O chalcogen-bond motifs were selected and truncated to model systems and seven more model systems were prepared by S-to-Se substitution. These systems were then subjected to analysis by quantum chemical (QM) methods-electrostatic potential, geometry optimisation or interaction energy calculations, including solvent effects. The QM calculations indicate that chalcogen bonding does indeed play a dominant role in stabilising some of the interaction motifs studied. We thus advocate further exploration of chalcogen bonding with the aim of potential future use in structure-based drug design., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Two binary boron hydrides (NH4)2B10H10 and Na2B12H12 and mono- and dicarboxy p- and m-carboranes (namely, 1-(COOH)-closo-1,7-C2B10H11, 1,12-(COOH)2-closo-1,12-C2B10H10 and 1,7-(COOH)2-closo-1,7-C2B10H10) were intercalated into ZnAl-layered double hydroxides (ZnAl-LDH) and into Zn5(OH)8(NO3)2·2H2O. The formed compounds were characterized using elemental analysis, thermogravimetry analysis, X-ray powder diffraction, infrared spectroscopy and solid state NMR. All the intercalated boron compounds are present in the interlayer space of the layered hosts as anions. It is presumed that in the case of B10H102-, B12H122- and 1,12-(COO)2-closo-1,12-C2B10H102-, the guest molecules form a monolayer, whereas in the case of 1-(COO)-closo-1,7-C2B10H111- and 1,7-(COO)2-closo-1,7-C2B10H102- a bilayer arrangement is more probable. In the case of 1,7-(COO)2-closo-1,7-C2B10H102-, the guest molecules are strongly interdigitated resulting in lowering of the interlayer distance. Two different modes of binding were found. Whereas the carboxylate derivatives of p- and m-carboranes are bonded through classical hydrogen bonds, the corresponding parent borane anions interact with the host structures by mainly dihydrogen bonding. In effect, both kinds of hydrogen bonding are mainly of an electrostatic nature. The dihydrogen bond is detected, e.g. in crystal engineering, and represents a driving force for interactions of boranes with biomolecules. Since the latter dicarboxylic acids were found to be superacids, their interactions with the host structures should be stronger than in the case of the benzoic and terephthalic acid intercalates.

Reported are procedures leading to the first types of methyl camouflaged dicarbadecaboranes with fewer than eleven vertices. The compounds contain the closo-1,6-C2B8 scaffolding inside the egg-shaped hepta - decamethyl sheath, which imparts unusually high air and solvolytic stability to all of these compounds.

Accurate prediction of protein-ligand binding affinities is essential for hit-to-lead optimization and virtual screening. The reliability of scoring functions can be improved by including quantum effects. Here, we demonstrate the ranking power of the semiempirical quantum mechanics (SQM)/implicit solvent (COSMO) scoring function by using a challenging set of 10 inhibitors binding to carbonic anhydrase II through Zn 2+ in the active site. This new dataset consists of the high-resolution (1.1-1.4 Å) crystal structures and experimentally determined inhibitory constant (K i ) values. It allows for evaluation of the common approximations, such as representing the solvent implicitly or by using a single target conformation combined with a set of ligand docking poses. SQM/COSMO attained a good correlation of R 2 of 0.56-0.77 with the experimental inhibitory activities, benefiting from careful handling of both noncovalent interactions (e.g. charge transfer) and solvation. This proof-of-concept study of SQM/COSMO ranking for metalloprotein-ligand systems demonstrates its potential for hit-to-lead applications., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This paper presents a systematic study of multicenter and classical bonding on a broad series of experimentally known heteroboranes covering closo, nido, arachno and hypho types of cages with incorporated tetrel, pnictogen or chalcogen heterovertices up to the third-row elements. The nature of bonding is studied using a novel quantum-chemical tool, the intrinsic atomic/bond orbital (IAO/IBO) approach, which provides a direct connection between quantum chemistry and chemical concepts. We also discuss how the computed IBO properties are related to molecular observables such as interatomic distances, molecular electrostatic potential surfaces and dipole moments.

11 B NMR chemical shifts of tricoordinated BX 3 and tetracoordinated BX 4 - compounds (X = H, CH 3 , F, Cl, Br, I, OH, SH, NH 2 , and CH═CH 2 ) were computed, and the shielding tensors were explored not only within the nonrelativistic GIAO approach but also by application of both relativistic ZORA computations including spin-orbit coupling as well as scalar nonrelativistic ZORA computations (BP86 level of density functional theory). The contributions of the spin-orbit coupling to the overall shieldings are decisive for X = Br and I in both series. No relationship was found between the 2p orbital occupancies or 1/ΔE (difference between LUMO and suitably occupied MO that can be coupled with LUMO) with the shielding tensors (or their principal values) in the BX 3 series. However, a multidimensional statistical approach known as factor analysis (frequently used in chemometrics) revealed that three factors account for 92% of the cumulative proportion of total variance. The main components of the first factor are occupancies in the 2p x and 2p y orbitals and 1/ΔE; the second factor is mainly the occupancy in the 2p z orbital and the inductive substituent parameters by Taft. Finally, the third factor consists exclusively (98.4%) of the electrostatic potential (V max ), which is directly related to the so-called π-hole magnitudes.

Rationale: The frequently used pesticide cyproconazole (Cyp) interacts with the essential elements commonly present in soil which play important roles in various enzymatic processes. These interactions predetermine the Cyp degradation pathways. We suggest a simple experimental and theoretical approach for the prediction of pesticide behavior., Methods: Cu/Cyp complexes are explored because of the typical Cu(II) reduction in complexes. Its level and the stability of the Cu-ligand bond depend on the type and the number of the surrounding ligands. Zn/Cyp complexes were compared as it is not expected that Zn(II) will reduce. The complexations were studied by means of electrospray ionization ion trap mass spectrometry and MS/MS collision-induced dissociations with comparative and explicative density functional theory calculations., Results: The Cyp ligand allows both Cu(II) reduction as well as, in specific cases, it protects the higher Cu oxidation state. The reduction is observed in the complexes with solely neutral Cyp where the number of ligands is below 3; a higher number protects the Cu(II) state. The metal atom binds to Cyp via N2 of the triazole ring as well as via π-electrons of the benzene ring; additional stabilization brings an interaction with the deprotonated OH group., Conclusions: The character of Cyp interactions with doubly charged metals (Cu(II), Zn(II)) clarified the creation of Cyp metabolites. The phenyl and triazole rings are bound to the metal cation and enable access for the isopropyl ring to be cleaved leaving the common metabolite (CAS Number: 58905-19-4)., (Copyright © 2017 John Wiley & Sons, Ltd.)

This paper presents a study of pnictogen bonding in a series of pyrazine•PnX 5 (Pn = P, As, Sb and X = F, Cl, Br) complexes. The whole series was studied computationally. Moreover, the pyrazine complexes with PCl 5 and SbCl 5 were prepared and characterized experimentally. It was found that the Pn-N distances are only slightly elongated when compared to the sum of covalent radii. The conformation of PnX 5 changed considerably upon the complex formation, which resulted in a significant change of the dipole moment of the PnX 5 fragment and a considerably more positive σ-hole on the pnictogen atom. Finally, interaction energies were decomposed in order to provide a deeper insight into the nature of the studied pnictogen-bonded complexes. Graphical abstract The conformation of PnX5 changed considerably upon the complex formation, which resulted in a considerably more positive σ-hole on the pnictogen atom.

We have prepared nido-7,8,9,11-Sb 2 C 2 B 7 H 9 , the first cluster with simultaneous Sb-B, Sb-C and Sb-Sb atom pairs with interatomic separations with magnitudes that approach the respective sums of covalent radii. However, the length of the Sb-Sb separation in this cluster is slightly less than the sum of the covalent radii. Quantum chemical analysis has revealed that the crystal packing of nido-7,8,9,11-Sb 2 C 2 B 7 H 9 is predominantly dictated by pnictogen (Pn) bonding, an unconventional σ-hole interaction. Indeed, the interaction energy of a very strong Sb 2 H-B Pn-bond in the nido-7,8,9,11-Sb 2 C 2 B 7 H 9 dimer exceeds -6.0 kcal mol -1 . This is a very large value and is comparable to the strengths of known Pn-bonds in Cl 3 Pnπ complexes (Pn = As, Sb).

General and reliable description of structures and energetics in protein-ligand (PL) binding using the docking/scoring methodology has until now been elusive. We address this urgent deficiency of scoring functions (SFs) by the systematic development of corrected semiempirical quantum mechanical (SQM) methods, which correctly describe all types of noncovalent interactions and are fast enough to treat systems of thousands of atoms. Two most accurate SQM methods, PM6-D3H4X and SCC-DFTB3-D3H4X, are coupled with the conductor-like screening model (COSMO) implicit solvation model in so-called "SQM/COSMO" SFs and have shown unique recognition of native ligand poses in cognate docking in four challenging PL systems, including metalloprotein. Here, we apply the two SQM/COSMO SFs to 17 diverse PL complexes and compare their performance with four widely used classical SFs (Glide XP, AutoDock4, AutoDock Vina, and UCSF Dock). We observe superior performance of the SQM/COSMO SFs and identify challenging systems. This method, due to its generality, comparability across the chemical space, and lack of need for any system-specific parameters, gives promise of becoming, after comprehensive large-scale testing in the near future, a useful computational tool in structure-based drug design and serving as a reference method for the development of other SFs., Competing Interests: The authors declare no competing financial interest.

Close B-Hπ contacts have recently been observed in crystallographic structures of Ir-dithiolene-phosphine complexes containing boron hydride cluster. This finding was interpreted using quantum chemical calculations as a new type of electrostatically driven nonclassical hydrogen bonding. However, such an explanation contradicts the wealth of evidence for unique noncovalent interactions of boron hydrides. Moreover, care must be exercised when computational methods are used to interpret new phenomena. Therefore, here, we cautiously examine the B-Hπ interaction by means of advanced quantum chemistry and disprove the claimed attractive electrostatic nature and rather define it as a nonspecific dispersion-driven contact. In summary, we present evidence that the crystallographically observed B-Hπ contacts do not constitute a novel type of hydrogen bonding of boron hydride clusters.