Aromatic Rings as Molecular Determinants for the Molecular Recognition of Protein Kinase Inhibitors

Protein kinases are key enzymes in many signal transduction pathways, and play a crucial role in cellular proliferation, differentiation, and various cell regulatory processes. However, aberrant function of kinases has been associated with cancers and many other diseases. Consequently, competitive inhibition of the ATP binding site of protein kinases has emerged as an effective means of curing these diseases. Over the past three decades, thousands of protein kinase inhibitors (PKIs) with varying molecular frames have been developed. Large-scale data mining of the Protein Data Bank resulted in a database of 2139 non-redundant high-resolution X-ray crystal structures of PKIs bound to protein kinases. This provided us with a unique opportunity to study molecular determinants for the molecular recognition of PKIs. A chemoinformatic analysis of 2139 PKIs resulted in findings that PKIs are “flat” molecules with high aromatic ring counts and low fractions of sp³ carbon. All but one PKI possessed one or more aromatic rings. More importantly, it was found that the average weighted hydrogen bond count is inversely proportional to the number of aromatic rings. Based on this linear relationship, we put forward the exchange rule of hydrogen bonding interactions and non-bonded π-interactions. Specifically, a loss of binding affinity caused by a decrease in hydrogen bonding interactions is compensated by a gain in binding affinity acquired by an increase in aromatic ring-originated non-bonded interactions (i.e., π–π stacking interactions, CH–π interactions, cation–π interactions, etc.), and vice versa. The very existence of this inverse relationship strongly suggests that both hydrogen bonding and aromatic ring-originated non-bonded interactions are responsible for the molecular recognition of PKIs. As an illustration, two representative PKI–kinase complexes were employed to examine the relative importance of different modes of non-bonded interactions for the molecular recognition of PKIs. For this purpose, two FDA-approved PKI drugs, ibrutinib and lenvatinib, were chosen. The binding pockets of both PKIs were thoroughly examined to identify all non-bonded intermolecular interactions. Subsequently, the strengths of interaction energies between ibrutinib and its interacting residues in tyrosine kinase BTK were quantified by means of the double hybrid DFT method B2PLYP. The resulting energetics for the binding of ibrutinib in tyrosine kinase BTK showed that CH–π interactions and π–π stacking interactions between aromatic rings of the drug and hydrophobic residues in its binding pocket dominate the binding interactions. Thus, this work establishes that, in addition to hydrogen bonding, aromatic rings function as important molecular determinants for the molecular recognition of PKIs. In conclusion, our findings support the following pharmacophore model for ATP-competitive kinase inhibitors: a small molecule features a scaffold of one or more aromatic rings which is linked with one or more hydrophilic functional groups. The former has the structural role of acting as a scaffold and the functional role of participating in aromatic ring-originated non-bonded interactions with multiple hydrophobic regions in the ATP binding pocket of kinases. The latter ensure water solubility and form hydrogen bonds with the hinge region and other hydrophilic residues of the ATP binding pocket.     

Correlations between the Major Amino Acids and Biochemical Blood Parameters of Pigs at Controlled Fattening Duration

Analytical control of protein and amino acid (AA) contents of animal tissues is an important problem in the fundamental and applied aspects. The aims of the work were the following: to measure the pig blood AAs; and to establish the correlations between AAs and biochemical parameters in dependence on the pig fattening duration. All 80 animals were divided onto 4 animal groups: 65, 72, 82, and 90 fattening days. The correlations between AAs and the total protein or its fractions (TP&F), nitrogen metabolites, carbohydrates, lipids, some enzymes in the pig blood for each of these animal groups obtained for the first time. The authors established the following total amounts of correlation coefficients (with reasonable p-values) in each of the group separately: group 1, 1* (p < 0.05); group 2, 0; group 3, 28* (p < 0.05) and 9** (p < 0.01); group 4, 28* (p < 0.05) and 25** (p < 0.01). Thus, about 82–90 days (groups 3 and 4) can be the optimal for the pig fattening, based on the correlation analysis for the numerous data of major AA and biochemical parameters of pig blood. These results can be useful for animal health monitoring and husbandry.     

Local aromaticity in polyacenes manifested by individual proton and carbon shieldings: DFT mapping of aromaticity

Exponential dependencies between locally calculated geometric and magnetic indexes of aromaticity, harmonic oscillator model of aromaticity (HOMA) and nucleus independent chemical shifts (NICS)(0), NICS(1) and NICS(1)zz, and the number of conjugated benzene rings in linear acenes, from benzene to decacene were observed at B3LYP/6-311+G** level of theory. Correlations between HOMA and NICS indexes showed exponential dependencies and were fitted with simple three-parameter function. Similar correlations between both indexes of aromaticity and proton and carbon nuclear isotropic shieldings of individual acene rings were observed. Contrary to proton data, the predicted ¹³C nuclear isotropic shieldings of carbon atoms belonging to inner rings in polyacenes were less shielded, indicating lower aromaticity and therefore, higher reactivity.     

Exploring the 2′-Hydroxy-Chalcone Framework for the Development of Dual Antioxidant and Soybean Lipoxygenase Inhibitory Agents

2′-hydroxy-chalcones are naturally occurring compounds with a wide array of bioactivity. In an effort to delineate the structural features that favor antioxidant and lipoxygenase (LOX) inhibitory activity, the design, synthesis, and bioactivity profile of a series of 2′-hydroxy-chalcones bearing diverse substituents on rings A and B, are presented. Among all the synthesized derivatives, chalcone 4b, bearing two hydroxyl substituents on ring B, was found to possess the best combined activity (82.4% DPPH radical scavenging ability, 82.3% inhibition of lipid peroxidation, and satisfactory LOX inhibition value (IC₅₀ = 70 μM). Chalcone 3c, possessing a methoxymethylene substituent on ring A, and three methoxy groups on ring B, exhibited the most promising LOX inhibitory activity (IC₅₀ = 45 μM). A combination of in silico techniques were utilized in an effort to explore the crucial binding characteristics of the most active compound 3c and its analogue 3b, to LOX. A common H-bond interaction pattern, orienting the hydroxyl and carbonyl groups of the aromatic ring A towards Asp768 and Asn128, respectively, was observed. Regarding the analogue 3c, the bulky (-OMOM) group does not seem to participate in a direct binding, but it induces an orientation capable to form H-bonds between the methoxy groups of the aromatic ring B with Trp130 and Gly247.     

Synthesis and Antinociceptive Effect of Some Thiazole-Piperazine Derivatives: Involvement of Opioidergic System in the Activity

In this study, we aimed to design and synthesize novel molecules carrying both the thiazole and piperazine rings in their structures and to investigate their antinociceptive activity. Targeted compounds were obtained by reacting thiosemicarbazide derivative and appropriate 2-bromoacetophenone in ethanol. The structures of the obtained compounds were determined using data from various spectroscopic methods (IR, ¹H-NMR, ¹³C-NMR, and LCMSMS). Experimental data from in vivo tests showed that test compounds 3a–3c, 3f, and 3g (50 mg/kg) significantly prolonged reaction times of animals in tail-clip and hot-plate tests compared to the controls, indicating that these compounds possess centrally mediated antinociceptive activities. Furthermore, these compounds reduced the number of writhing behaviors in the acetic acid-induced writhing tests, showing that the compounds also possess peripheral antinociceptive activity. In the mechanistic studies, naloxone pre-treatments abolished the antinociceptive activities of compounds 3a–3c, 3f, and 3g, indicating that opioidergic mechanisms were involved in their antinociceptive effects. Molecular docking studies demonstrating significant interactions between the active compounds and µ- and δ-opioid receptor proteins supported the pharmacological findings. This study is the first showing that molecules designed to bear thiazole and piperazine moieties together on their structure exert centrally and peripherally mediated antinociceptive effects by activating the opioid system.     

Determination of the bond-angle distribution in vitreous B2O3 by B double rotation (DOR) NMR spectroscopy

The B–O–B bond angle distributions for both ring and non-ring boron sites in vitreous B₂O₃ have been determined by ¹¹B double rotation (DOR) NMR and multiple-quantum (MQ) DOR NMR. The [B₃O₆] boroxol rings are observed to have a mean internal B–O–B angle of 120.0±0.7° with a small standard deviation, σ_R=3.2±0.4°, indicating that the rings are near-perfect planar, hexagonal structures. The rings are linked predominantly by non-ring [BO₃] units, which share oxygens with the boroxol ring, with a mean B_ring–O–B_non-ring angle of 135.1±0.6° and σ_NR=6.7±0.4°. In addition, the fraction of boron atoms, f, which reside in the boroxol rings has been measured for this sample as f=0.73±0.01.     

运用密度泛函活性理论的信息论方法研究苯并富烯衍生物的芳香性

文献中已有越来越多的芳香性体系被发现,同时也有越来越多的芳香性指标被提出来,但是如何解释芳香化合物稳定性的起源以及理解芳香性的本质仍然是当今理论化学中一个悬而未决的难题。运用我们新近提出的密度泛函活性理论信息论方法,不久前我们曾对一系列富烯衍生物进行了系统研究并得到了一个全新的认识。本文进一步探讨苯并富烯衍生物的芳香性行为,目的在于考察一个或多个苯环与富烯连接之后其芳香性发生变化的情况。运用香农熵,费舍尔信息,Ghosh-Berkowitz-Parr熵,Onicescu信息能,信息增益,以及相对Rényi熵六个信息量,和四种芳香指标,ASE,HOMA,FLU和NICS,我们系统地研究了信息量和芳香性指标在单、双、三苯并富烯衍生物中的相关性。我们发现,不管是否有苯环与富烯相连,芳香指标和信息量的交叉相关性都是一样的。这表明,虽然苯环本身具有芳香性,但苯环与富烯相连并不能改变富烯的芳香性与反芳香性本质。苯并富烯衍生物与富烯衍生物的芳香性和反芳香性一致。苯并富烯衍生物的芳香性和反芳香性完全取决于富烯本身的芳香性和反芳香性。这些结果为认识和理解复杂体系芳香性和反芳香性起源和本质将提供有益的启示。     

Studies on the stability of four-membered ring chelates Part V. The stability of dialkyl dithiocarbamate chelates

This paper systematically studies the structure and the internal mechanism of the stability of sulphur-coordinated four-membered rings in chelates of dialkyl dithiocarbamate. It was found that the conjugated π electron structure of the free ligand is Π₄⁶, while in the metal chelate it is Π₄⁴. The stable chelates have strong σ- and π-coordinated bonds. The actual strain of the sulphur-coordinated four-membered ring in chelates is not as strong as assumed. It mainly depends on the atomic radius of the metal. The stronger the electronegativity of the metal, the stronger the π-coordinated bond. The stabler the four-membered ring, the weaker the intensity of the C-S vibrational band.     

Analysis of electron delocalization in aromatic systems: individual molecular orbital contributions to para-delocalization indexes (PDI)

Our research group has recently defined two new aromaticity indexes based on the analysis of electron delocalization in aromatic species using the quantum theory of atoms-in-molecules. One of these indexes is the para-delocalization index (PDI) that measures the electronic delocalization between para-related carbon atoms in six-membered rings. In this paper, we show that this index can be partitioned into individual molecular orbital contributions. We have applied this PDI decomposition to several polycyclic aromatic hydrocarbons showing that this partitioning provides new insight into the origin of aromaticity.     

β-Cyclodextrin Inclusion Complexes with Catechol-Containing Antioxidants Protocatechuic Aldehyde and Protocatechuic Acid—An Atomistic Perspective on Structural and Thermodynamic Stabilities

Protocatechuic aldehyde (PCAL) and protocatechuic acid (PCAC) are catechol derivatives and have broad therapeutic effects associated with their antiradical activity. Their pharmacological and physicochemical properties have been improved via the cyclodextrin (CD) encapsulation. Because the characteristics of β-CD inclusion complexes with PCAL (1) and PCAC (2) are still equivocal, we get to the bottom of the inclusion complexation by an integrated study of single-crystal X-ray diffraction and DFT full-geometry optimization. X-ray analysis unveiled that PCAL and PCAC are nearly totally shielded in the β-CD wall. Their aromatic rings are vertically aligned in the β-CD cavity such that the functional groups on the opposite side of the ring (3,4-di(OH) and 1-CHO/1-COOH groups) are placed nearby the O6–H and O2–H/O3–H rims, respectively. The preferred inclusion modes in 1 and 2 help to establish crystal contacts of OH⋅⋅⋅O H-bonds with the adjacent β-CD OH groups and water molecules. By contrast, the DFT-optimized structures of both complexes in the gas phase are thermodynamically stable via the four newly formed host–guest OH⋯O H-bonds. The intermolecular OH⋅⋅⋅O H-bonds between PCAL/PCAC 3,4-di(OH) and β-CD O6–H groups, and the shielding of OH groups in the β-CD wall help to stabilize these antioxidants in the β-CD cavity, as observed in our earlier studies. Moreover, PCAL and PCAC in distinct lattice environments are compared for insights into their structural flexibility.     

Hydrogen and Lithium Bonds—Lewis Acid Units Possessing Multi-Center Covalent Bonds

MP2/aug-cc-pVTZ calculations were carried out on complexes wherein the proton or the lithium cation is located between π-electron systems, or between π-electron and σ-electron units. The acetylene or its fluorine and lithium derivatives act as the Lewis base π-electron species similarly to molecular hydrogen, which acts as the electron donor via its σ-electrons. These complexes may be classified as linked by π-H∙∙∙π/σ hydrogen bonds and π-Li∙∙∙π/σ lithium bonds. The properties of these interactions are discussed, and particularly the Lewis acid units are analyzed, because multi-center π-H or π-Li covalent bonds may occur in these systems. Various theoretical approaches were applied here to analyze the above-mentioned interactions—the Quantum Theory of Atoms in Molecules (QTAIM), the Symmetry-Adapted Perturbation Theory (SAPT) and the Non-Covalent Interaction (NCI) method.     

π-Stacking Stopper-Macrocycle Stabilized Dynamically Interlocked [2]Rotaxanes

The synthesis of mechanically interlocked molecules is valuable due to their unique topologies. With π-stacking intercomponent interaction, e.g., phenanthroline and anthracene, novel [2]rotaxanes have been synthesized by dynamic imine clipping reaction. Their X-ray crystal structures indicate the π-stackings between the anthracene moiety (stopper) on the thread and the (hetero)aromatic rings at the macrocycle of the rotaxanes. Moreover, the length of glycol chains affects the extra π-stacking intercomponent interactions between the phenyl groups and the dimethoxy phenyl groups on the thread. Dynamic combinatorial library has shown at best 84% distribution of anthracene-threaded phenanthroline-based rotaxane, coinciding with the crystallography in that the additional π-stacking intercomponent interactions could increase the thermodynamic stability and selectivity of the rotaxanes.     

Ion-beam irradiation effects on polyimide-UV–vis and infrared spectroscopic study

Ion-beam irradiation effects on polyimide, Kapton™, were studied with respect to optical and electronic properties. Stack films of Kapton™ (12.5 μm thick) were irradiated to various ion beams in air or vacuo at room temperature and subjected to ultraviolet–visible (UV–vis) spectroscopy, and change in absorbance and energy gap is discussed. The UV–vis absorption spectrum, which is assigned to the transition of electrons in benzene rings from π to π* orbital, upon He²⁺ (6 MeV/u) irradiation in air, shifted towards longer wavelength direction for all cases, and the shift was more obvious for higher linear energy transfer (LET) ion beams. The energy gap of the transition was estimated, and the H⁺ and He²⁺ ion beams caused little change in the transition energy gap Eg, while the heavier ions such as C⁶⁺ and Si¹⁴⁺ caused more significant decrease. This decrease is assumed to the structural changes around benzene rings, and the infrared spectroscopy revealed breakage in imide groups next to benzene ring in the repeating unit of polyimide.     

A Quantum-Chemical Study on the Photochemical Properties of Azides of a Series of Heteroarenes from Pyridine to Dibenzoacridine in Neutral and Protonated Forms

Molecules of a series of heteroaromatic azides in the ground (S ₀) and the lowest excited singlet (S ₁) states were calculated by the PM3 semiempirical method. It was shown that in the S ₀ state, the azide group in all the azides has quasi-linear geometry and a significant positive charge on the two terminal nitrogen atoms. The azide photoactivity is determined by the population of the σ _NN ^* orbital in the excited state, which is unoccupied in the ground state. The population of this orbital was found to depend on the size and charge of the aromatic π system. For the initial members of this azide series, the σ _NN ^* orbital is populated in both neutral and protonated forms. This is consistent with the experimental data and means that these azides are photoactive. With an increase in the size of the aromatic system, the energetic gap between the σ _NN ^* orbital and LUMO increases. As a result, the σ _NN ^* orbital is not populated in the S ₁ state when a particular threshold size of the π system is achieved, and the azide becomes photo-inactive.__________Translated from Khimiya Vysokikh Energii, Vol. 39, No. 4, 2005, pp. 259–266.Original Russian Text Copyright © 2005 by Budyka, Oshkin.     

Complementary,Cooperative Ditopic Halogen Bonding and Electron Donor-Acceptor π-π Complexation in the Formation of Cocrystals

This study expands and combines concepts from two of our earlier studies. One study reported the complementary halogen bonding and π-π charge transfer complexation observed between isomeric electron rich 4-N,N-dimethylaminophenylethynylpyridines and the electron poor halogen bond donor, 1-(3,5-dinitrophenylethynyl)-2,3,5,6-tetrafluoro-4-iodobenzene while the second study elaborated the ditopic halogen bonding of activated pyrimidines. Leveraging our understanding on the combination of these non-covalent interactions, we describe cocrystallization featuring ditopic halogen bonding and π-stacking. Specifically, red cocrystals are formed between the ditopic electron poor halogen bond donor 1-(3,5-dinitrophenylethynyl)-2,4,6-triflouro-3,5-diiodobenzene and each of electron rich pyrimidines 2- and 5-(4-N,N-dimethyl-aminophenylethynyl)pyrimidine. The X-ray single crystal structures of these cocrystals are described in terms of halogen bonding and electron donor-acceptor π-complexation. Computations confirm that the donor-acceptor π-stacking interactions are consistently stronger than the halogen bonding interactions and that there is cooperativity between π-stacking and halogen bonding in the crystals.     

H NMR of the α,α′-bipyridine and o-phenanthroline adducts of n-butyltin trichloride

¹H NMR spectra of the α,α′-bipyridine adduct of n-BuSnCl₃ indicated the non-equivalence of the two pyridine rings. In particular the signals of the proton on the carbon atom adjacent to the two nitrogen atoms were widely separated. Similar spectral behavior was observed in the o-phenanthroline adduct. These adducts therefore are concluded to have the n-butyl group lying on the N---Sn---N plane of the hexacoordinated complexes. The configurational rearrangement of these adducts was markedly accelerated in the presence of excess n-BuSnCl₃.     

Well-defined aqueous nanoassemblies from amphiphilic meta-terphenyls and their guest incorporation

Spherical molecular assemblies with diameters of ∼2 nm were quantitatively formed in water from new amphiphilic meta-terphenyls with two hydrophilic pendants at the central benzene ring. Whereas intermolecular interactions between small aromatic rings are typically weak, the obtained nanoassemblies are stable enough at wide-ranging concentrations and mostly remain intact even in the presence of similar nanoassemblies with polyaromatic frameworks. The nanoassembly with pentamethyl-substituted terminal benzene rings provides superior host capability for fluorescent dyes in water.     

An ab initio study of electronic spectra and excited-state properties of 7-azaindole in vapour phase and aqueous solution

The geometries of 7-azaindole (7AI), its tautomer (7AT), and 7AI–H₂O and 7AT–H₂O complexes were optimised in the ground state and some low-lying singlet excited states using the 3-21G basis set. Differences of total energies of the optimised ground and excited states and the vertical excitation energies of these systems were used to explain the observed electronic spectra. Effect of solvation of these systems in bulk water was studied using the polarized continuum model (PCM). The mode of binding of a water molecule in the S₂(n–π^*) excited state of 7AI was found to be quite different from those in its ground and π–π^* excited states. It is shown that crossing of the lowest two singlet excited-state potential surfaces S₁(π–π^*) and S₂(n–π^*) of 7AI occurs in the vapour phase under geometry relaxation while on interaction with water, the S₂(n–π^*) excited state is raised up appreciably going even above the S₃(π–π^*) excited state. Ground- and excited-state molecular electrostatic potential mapping was carried out, which led to valuable information regarding the nature of excited states of the above-mentioned systems.