Dimeric Cavity Research Articles

In silico analysis of SOD1 aggregation inhibition modes of tertiary amine pyrazolone and pyrano coumarin ferulate as ALS drug candidates.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, the familial form (fALS) of which is often cognate to mutations in the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) leading to misfolding and aggregation. Two small molecules, a tertiary amine pyrazolone (TAP) and a pyrano coumarin ferulate (PCF) were suggested to be ALS drug candidates following experimental observation of their ability to inhibit SOD1 protein misfolding and aggregation. The present work aims at computational investigation of these experimentally proposed drug candidates to gain insight into their mechanism of SOD1 misfolding and aggregation inhibition. On the basis of molecular docking, molecular dynamics simulation, MM-PBSA and per-residue energy decomposition analysis, we examined the specific interactions of TAP and PCF with three probable binding sites of SOD1, namely, dimeric interface cavity, W32 and, UMP binding sites. Results suggest that the binding of TAP at W32 and at UMP sites are least probable due to absence of any favorable interaction. The binding of TAP to dimeric cavity is also unstable due to strong unfavorable interactions. In case of PCF, binding at the UMP site is least probable while binding at dimeric cavity is accompanied by unfavorable interactions. PCF, however, exhibits stable binding with the W32 binding site of SOD1 by stabilizing the solvent accessible hydrophobic residues, which otherwise would have acted as contact points for aggregation. Thus the results imply that compound PCF functions as an inhibitior of SOD1 misfolding/aggregation through direct interaction with the protein SOD1 at the W32 binding site. However, TAP is likely to act as an inhibitor through a different mechanism rather than direct interaction with the protein SOD1. These results apart from reinforcing previous experimental findings, shed light on the probable mechanism of action of the proposed drug candidates.

Pseudo-polymorphism of a camphor α-cyclodextrin complex

Crystalline products of vapor diffusion of an alcoholic solution of 1R,4R-camphor into an aqueous solution of α-cyclodextrin were prepared and subjected to X-ray structure analysis. Two different forms were obtained: a dimeric cavity formed by head-to-head association of cyclodextrin (phase A), and a complex set of monomeric cavities (phase B). Both contain camphor molecules orientationally disordered inside cavities. The structures are solvated by mixtures of water and ethanol. The structures significantly differ in chemical stabilities. Whilst phase A is relatively stable with respect to guest desorption, phase B rapidly reacts to change of its chemical environment manifested by cracking of crystals in solution. The phenomenon has been recorded and a short movie is included in the supplementary data.

Inclusion Scenarios and Conformational Flexibility of the SSRI Paroxetine as Perceived from Polymorphism of β-Cyclodextrin-Paroxetine Complex.

Depression, a global mental health problem, is prevalent during the coronavirus disease 2019 (COVID-19) pandemic and can be efficiently treated by selective serotonin reuptake inhibitors (SSRIs). Our study series aims at forwarding insights on the β-cyclodextrin (β-CD)–SSRI inclusion complexes by X-ray crystallography combined with density functional theory (DFT) calculation. Here, we report a new crystal form (II) of the 1:1 β-CD–paroxetine (PXT) complex, which is inspired by the reported 2:1 β-CD–PXT complex (crystal form I), reflecting an elusive phenomenon of the polymorphism in CD inclusion complexes. The β-CD–PXT polymorphism stems from the PXT conformational flexibility, which is defined by torsion angles κ, ε around the -CH2–O- group bridging the A- and C–D-rings, of which those of PXT in I and II are totally different. While PXT (II) in an open V-shaped conformation that has the B-ring shallowly inserted in the β-CD cavity, PXT (I) in a closed U-shaped structure is mostly entirely embedded in the β-CD dimeric cavity, of which the A-ring is deeply inserted in the main β-CD cavity. However, PXT molecules in both crystal forms are similarly maintained in the CD cavity via host–guest N–H···O5/O6 H-bonds and C/O–H···π(B/C) interactions and β-CDs have similar 3D arrangements, channel (II) vs. screw-channel (I). Further theoretical explorations on the β-CD–PXT thermodynamic stabilities and the PXT conformational stabilities based on their potential energy surfaces (PESs) have been completed by DFT calculations. The 2:1 β-CD–PXT complex with the greater presence of dispersion interactions is more energetically favorable than the unimolar complex. Conversely, whereas free PXT, PXT (II) and PXT in complex with serotonin transporter are more energetically stable, PXT (I) is least stable and stabilized in the β-CD cavity. As SSRIs could lessen the COVID-19 severity, the CD inclusion complexation not only helps to improve the drug bioavailability, but also promotes the use of antidepressants and COVID-19 medicines concurrently.

Advancing insights on β-cyclodextrin inclusion complexes with SSRIs through lens of X-ray diffraction and DFT calculation

Depression—the global crisis hastened by the coronavirus outbreak, can be efficaciously treated by the selective serotonin reuptake inhibitors (SSRIs). Cyclodextrin (CD) inclusion complexation is a method of choice for reducing side effects and improving bioavailability of drugs. Here, we investigate in-depth the β-CD encapsulation of sertraline (STL) HCl (1) and fluoxetine (FXT) HCl (2) by single-crystal X-ray diffraction and DFT complete-geometry optimization, in comparison to the reported complex of paroxetine (PXT) base. X-ray analysis unveiled the 2:2 β-CD–STL/FXT complexes with two drug molecules inserting their halogen-containing aromatic ring in the β-CD dimeric cavity, which are stabilized by the interplay of intermolecular O2–H⋯N1–H⋯O3 H-bonds, C3/C5–H⋯π and halogen⋯halogen interactions. Similarly, the 1:1 β-CD–tricyclic-antidepressant (TCA) complexes have an exclusive inclusion mode of the aromatic ring, which is maintained by C3/C5–H⋯π interactions. By contrast, the 2:1 β-CD–PXT complex has a total inclusion that is stabilized by host–guest O6–H⋯N1–H⋯O5 H-bonds and C3–H⋯π interactions. The inherent stabilization energies of 1 and 2 evaluated using DFT calculation suggested that the improved thermodynamic stabilities via CD encapsulation facilitates the reduction of drug side effects. Moreover, the SSRI conformational flexibilities are thoroughly discussed for understanding of their pharmacoactivity.

X-ray crystallography and molecular dynamics studies of the inclusion complexes of geraniol in β-cyclodextrin, heptakis (2,6-di-O-methyl)-β-cyclodextrin and heptakis (2,3,6-tri-O-methyl)-β-cyclodextrin

Abstract The inclusion of the linear monoterpene, geraniol (gr) in β-cyclodextrin (β-CD), heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD) has been studied by X-ray crystallography and Molecular Dynamics simulations. The gr/β-CD complex crystallizes as a head-to-head dimer in the P21 space group stacking along the crystallographic a-axis in a channel packing mode. Two guest molecules are accommodated almost axially inside the dimeric cavity with their aliphatic ends laying in the interface region of the dimer facing each other and their hydroxylic ends protruding from the narrow β-CD rims. The guest molecules of the adjacent dimers in a channel are interconnected via CH ⋯O and hydrogen bonds forming an internal wire. Both the gr/DM-β-CD and gr/TM-β-CD complexes crystallize in the P212121 space group and stack along the crystallographic b-axis in a head-to-tail manner. DM-β-CD host adopts the conformation of a rigid and well-shaped open cone upon complexation, in which the guest molecule is found highly disordered over 5 sites with varying depths of immersion. The gr/DM-β-CD complex units are arranged in channels and the gr molecules within these channels are also interconnected via CH ⋯O bonds. On the other hand, TM-β-CD host is found severely distorted adopting a ‘closed’ cup-shaped conformation. The guest is partially encapsulated in the wide rim of TM-β-CD and it is found disordered over 3 sites with quite different orientations. The complex units are arranged forming screw channels, with the main part of the guest laying outside the host cavity and filling the intermediate space between the succeeding hosts. The MD analysis based on the crystallographically determined structures sheds light on the dynamic behavior of the geraniol upon complexation with these hosts, its conformation variations and the interconversion of the inclusion modes in solution. Finally, MM/GBSA-calculations revealed that the ascending order in binding affinity ΔG values is: gr/TM-β-CD

Entrapment of a linear water pentamer into a uranyl-salophen dimer in the solid state

ABSTRACTIn the solid state, uranyl-salophen complex 1, decorated with bipyridyl sidearms, self-assembles from moist acetonitrile into dimeric species displaying a confined water pentamer, as observed by X-ray diffraction on single crystals. The linear water cluster is incarcerated within the dimeric cavity by coordination to the Lewis acidic uranyl centres and by a network of hydrogen bonds established with the pyridinic nitrogen atoms on the sidearms.

Inclusion complex of β-cyclodextrin with coffee chlorogenic acid: new insights from a combined crystallographic and theoretical study.

This work reports the elusive structural evidence for the [4]pseudorotaxane of β-cyclodextrin (β-CD) with coffee chlorogenic acid (CGA), a conjugate of caffeic acid (CFA) and quinic acid (QNA). A single-crystal X-ray structure analysis of the inclusion complex β-cyclodextrin-chlorogenic acid-water (2/2/17), 2C42H70O35·2C16H18O9·17H2O, reveals that CGA threads through β-CD and assembles via O-H...O hydrogen bonds and parallel-displaced π-π interactions in the twofold symmetry-related dimer yielding a [4]pseudorotaxane, which is crystallographically observed for the first time in CD inclusion complexes. The encapsulation of the aromatic ring and C=C-C(=O)O chain in the β-CD dimeric cavity indicates that the CFA moiety plays a determinant role in complexation. This is in agreement with the DFT-derived relative thermodynamic stabilities of the trimodal β-CD-CGA inclusion complexes, that is, β-CD complexed with different CGA components: C=C-C(=O)O chain > cyclohexane ring > aromatic ring. The complexation stability is further enhanced in the dimeric β-CD-CGA complex, with the CFA moiety totally enclosed in the β-CD dimeric cavity.

Crystallographic and theoretical studies of an inclusion complex of β-cyclodextrin with fentanyl

The crystal structure of an inclusion complex of β-cyclodextrin (β-CD) with fentanyl was determined by single crystal X-ray diffraction analysis. The crystal belongs to the triclinic space group P1 and the complex comprises one fentanyl, two β-CD, and several water molecules. β-CD and fentanyl form a host-guest inclusion complex at a ratio of 2:1 and the asymmetric unit of the complex contains two host molecules (β-CDs) in a head-to-head arrangement that form dimers through hydrogen bonds between the secondary hydroxyl groups of β-CD and one guest molecule. Fentanyl is totally contained within the β-CD cavity and the structure of the phenylethyl part of fentanyl inside the dimeric cavity of the complex is disordered. Furthermore, theoretical molecular conformational calculations were conducted to clarify the mobility of the guest molecule in the β-CD cavity using CONFLEX software. Crystal optimization and crystal energy calculations were also conducted. The results of the theoretical calculations confirmed that the conformation of disorder part 1, which was high in occupancy by crystal structure analysis, was more stable. The phenylethyl part of fentanyl existed in several stable conformations.

Structural studies of the inclusion complexes of the (+)- and (−)-borneol enantiomers in α- and β-cyclodextrin

The crystal structures of the inclusion compounds of the (+)- and (−)-borneol enantiomers in α- and β-cyclodextrin (CD) were determined by X-ray crystallography at about 1 A resolution. In all the cases, the α- or β-CDs form head-to-head dimers arranged in a “chessboard” crystal packing mode. In the cases of the (+)- and (−)-borneol/αCD inclusion complexes, one guest molecule is accommodated inside the formed dimeric cavity (2:1 host:guest stoichiometry) disordered over two and three sites respectively. Ιn the cases of the (+)- and (−)-borneol/βCD inclusion complexes, a highly disordered guest molecule is located inside the dimeric cavity and two additional guest molecules lay at the rims of the primary hydroxyls of the dimer (2:3 host:guest stoichiometry) participating in the crystal contacts by forming H-bonds with external water molecules and –OH groups of the β-CDs of the adjacent dimers. Regarding the ability of α- and β-CD for borneol enantioseparation, the crystallographic analysis shows that no significant differences concerning the inclusion geometry and crystal packing are observed between the inclusion complexes of the borneol enantiomers with the same host CD.

Inclusion compounds of plant growth regulators in cyclodextrins, part VII: study of the crystal structures of 2-naphthylacetic acid encapsulated in β-cyclodextrin and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin complexes by X-ray crystallography

The crystal structures of the β-naphthylacetic acid (2NAA)/β-cyclodextrin (β-CD) and the 2NAA/heptakis(2,3,6-tri-O-methyl)-β-CD (TMβCD) complexes are reported. The 2NAA/β-CD complex crystallizes in the triclinic system forming a dimer inside the cavity of which two 2NAA molecules disordered over two sites are located. The dimers are stacked along the c axis according to the channel packing mode forming a nanotube which resembles a wireway as it contains guest molecules linked by π–π interactions inside each dimeric cavity and by H-bonds between the adjacent dimers. The 2NAA/TMβCD complex crystallizes in the orthorhombic space group P212121. Its asymmetric unit contains one host, one guest distributed over two sites and one water molecule having a low occupancy factor. The complexes are packed in a head-to-tail mode forming a screw channel along the b axis. The carboxyl group of the guest protrudes towards the “free” space between the complexes and is H-bonded to the water molecule which in turn is H-bonded to the O5n atom of the host of the subsequent complex. The orientation of the guest molecule in the 2NAA/β-CD complex has been found opposite to that of the guest in the 2NAA/TMβCD complex probably due to the formation of dimers and the π–π interactions between the naphthalene moieties of the encapsulated molecules inside the dimeric cavity.

Inclusion Compounds of Plant Growth Regulators in Cyclodextrins. Part VI. Study of the Inclusion Compound of MCPA in β-Cyclodextrin by X-Ray Crystallography

The structure of the 4-chloro-2-methylphenoxyacetic acid (MCPA) inclusion compound in β-Cyclodextrin (β-CD) has been investigated by X-ray crystallography. The inclusion complex crystallizes in the P21 space group with unit cell dimensions a = 15.860(2) A, b = 24.275 (5) A, c = 19.334(6) A and β = 108.80(3)°. Its asymmetric unit contains two β-CD molecules which host two disordered MCPA guest molecules (2:2 host:guest stoichiometry) occupying overall five sites. It also contains 16.13 water molecules distributed over 36 sites. One water molecule is entrapped inside the dimeric cavity, forming a hydrogen bond with the chlorine atom of a guest. The two complexes of the asymmetric unit are located alongside and they form head-to-head dimers with the symmetry related complexes by the 2-fold screw axis (b-axis). The dimers form channels developed along the a-axis.

Different metal-ion-induced dimeric self-assembling cavities based on thiacalix[4]benzocrown-4 isomers

To construct the self-assembly of metal-ion-induced well-ordered architectures based on calixcrowns, isomeric thiacalix[4]benzocrowns-4 1 and 2 with rigid and small crown units were employed as the new scaffolds. They all show remarkable selectivity for Ag(+) and their complexation ability towards Ag(+) results in two novel dimeric aggregates of calixcrowns, which were first evidenced by ESI-MS, (1)H and DOSY-NMR spectra. Ultimately, X-ray diffraction experiments confirmed unambiguously the existence of the two metal-ion-induced dimers in lower rim/lower rim mode, and showed that dimerization of calixcrown 1 or 2 in the presence of Ag(+) could form dimeric supramolecular cavity with a small inner room. Moreover, the positional isomerism of their crown units (o-benzocrown unit for ligand 1 and m-benzocrown unit for 2) led to a dramatic change in the configuration of the two dimeric cavities 1·Ag(+) and 2·Ag(+). For dimeric cavity 1·Ag(+), two silver centers seamed two thiacalix[4]crown molecules together and resided at the edge of the dimeric self-assembling cavity; for dimeric cavity 2·Ag(+), one Ag(+) stitched two thiacalixcrowns together and was encapsulated in the center of the self-assembling cavity, while the other Ag(+) is tied down to one end of the dimer. Consequently, as a result of the different construction of dimeric cavities 1·Ag(+) and 2·Ag(+) the extended structures of the complexes are also different. The neighbour self-assembling cavities 1·Ag(+) are mutually oriented side-by-side and form a 1-D rectilineal polymeric chain. While, the neighbour self-assembling cavities 2·Ag(+) arrange themselves in a typical head-to-tail fashion to form a zig-zag polymeric chain.

X-ray crystallographic structure of the two-to-one α-cyclodextrin-acetone. 9H2O compound

Abstract An inclusion complex of acetone with α-cyclodextrin (α-CD) has been prepared in aqueous solution containing AG+ ions. The crystal structure of the complex has been determined by single crystal X-ray diffraction. Crystal data: triclinic, space group P1, Z = 1, a = 13.852(1), b = 13.878(1), c = 15.719(1) A, α = 93.01(1), β = 91.98(1), γ = 119.32(1)° and R = 0.069 for 6092 observed MoKα reflections with I > 3σ(I). This crystalline form is of the dimeric-type structure which normally occurs for ionic guest molecules. The dimers are stacked along the c axis to form an ‘endless head-to-head’ channel. Nine water molecules fill the intermolecular space outside the dimeric cavity and contribute to reinforce the cohesion between the channels which are in a pseudo-hexagonal arrangement. The acetone molecule is encapsulated within the cavity of the dimer. Molecular graphics analysis of difference Fourier maps suggests that the acetone molecule is situated in several partially occupied sites forming an infini...