Low-energy Conformations Research Articles

Enhancing the Thermal Stability of Organic Solar Cells by Locking Morphology with Ethyl Cellulose Additive

The morphology of active layer of the organic solar cells (OSCs) tends to transition toward its lowest energy conformation under thermal stress, significantly limiting the stability of OSCs. In this study, ethyl cellulose (EC) is utilized as an additive in the active layer of the typical PM6:Y6 and other systems. Due to the strong interaction between the hydroxyl groups of EC and the heteroatoms in the organic semiconductors, their bulk heterojunction nanomorphology is locked, thereby enhancing device thermal stability. Under thermal stress at 65 °C for 1,000 h, the PM6:Y6 device incorporating EC demonstrates excellent stability nearly without performance loss. Furthermore, compared to the control device, the device exhibits improved thermal stability under a range of more stringent aging conditions. Additionally, the EC additive shows broad applicability in various active layer systems, effectively enhancing their thermal stability. This work offers a promising approach for developing stable nanomorphology structures in OSCs.

Mechanisms of Peptide Agonist Dissociation and Deactivation of Adhesion G-Protein-Coupled Receptors.

Adhesion G protein-coupled receptors (ADGRs) belong to Class B2 of GPCRs and are involved in a wide array of important physiological processes. ADGRs contain a GPCR autoproteolysis-inducing domain that is proximal to the receptor N-terminus and undergoes autoproteolysis during the biosynthesis to generate two fragments: the N-terminal fragment (NTF) and the C-terminal fragment (CTF). Dissociation of NTF reveals a tethered agonist to activate the CTF of ADGRs for G protein signaling. Synthetic peptides that mimic the tethered agonist can also activate ADGRs. However, mechanisms of peptide agonist dissociation and the deactivation of ADGRs remain poorly understood. In this study, we have performed all-atom enhanced sampling simulations using a novel protein-protein interaction Gaussian-accelerated molecular dynamics (PPI-GaMD) method on the ADGRG2-IP15 and ADGRG1-P7 complexes. The PPI-GaMD simulations captured the dissociation of the IP15 and P7 peptide agonists from their target receptors. We were able to identify important low-energy conformations of ADGRG2 and ADGRG1 in the active, intermediate, and inactive states, as well as different states of the peptide agonists IP15 and P7 during dissociation. Therefore, our PPI-GaMD simulations have revealed dynamic mechanisms of peptide agonist dissociation and deactivation of ADGRG1 and ADGRG2, which will facilitate the rational design of peptide regulators of the two receptors and other ADGRs.

Arrangement of Azidomethyl Group in Lupinine Azide: Structural and Spectroscopic Properties

Quinolizidine derivatives are an important class of substances that are used in the pharmaceutical industry. In previous studies, the synthesis of these substances is carried out using lupinine azide (IUPAC: 1-(azidomethyl)octahydro-2H-quinolizine), which is often used to obtain new biologically active compounds. In this regard, its structural characterization is critically important. In this work, the conformational diversity of the molecular structure of this compound has been studied. It is shown that the structure with the axial position of the methyl azide group contains a number of low-energy conformer states with energies higher than the ground state by 0.15–0.60 kcal/mol. Such structural ambiguity should manifest itself in the chemical reactions and biological activity of lupinine azide. The spectroscopic properties of the conformers were studied by modeling chemical shifts for carbon and hydrogen atoms, as well as by simulating IR absorption spectra. An analysis of the most specific spectroscopic features of all of the conformers was carried out. Based on the correlation of the theoretical results and the experimental spectroscopic data, a conclusion was made for the first time regarding the most probable conformational states in the solution.

Tunneling and conformational preferences in racemic- and meso-2,4-pentanediol: A rotational spectroscopic and theoretical investigation.

The rotational spectra of a mixture of 2,4-pentanediol (PDL) isomers, comprising both the meso isomers [(2R, 4S) and (2S, 4R)] and the racemic isomers [(2R, 4R) and (2S, 4S)], were recorded using a chirped-pulse Fourier transform microwave spectrometer coupled to a supersonic jet expansion. The conformational landscapes of meso- and racemic-PDL were examined using the Conformer-Rotamer Ensemble Sampling Tool and high-level quantum chemical calculations, generating 26 and 25 conformers, respectively. Five sets of rotational transitions were observed and assigned, with two attributed to meso-PDL and the remaining three attributed to racemic-PDL. Furthermore, tunneling splittings were observed for both meso-PDL conformers, and the nudged elastic band method was utilized to map the corresponding tunneling pathways and obtain tunneling barriers. To rationalize relative abundances of the observed conformers and the non-observation of other low-energy conformers, possible conversion pathways among meso-PDL conformers and racemic-PDL conformers were also explored. Finally, ten carbon-13 isotopologues, five from each of the lowest-energy meso- and racemic-PDL conformers, were detected in natural abundance and used to establish the corresponding geometries. These results offer valuable insights into the stereoisomeric behaviors and conformational preferences within flexible diols.

DFT Calculations of 1H and 13C NMR Chemical Shifts of Hydroxy Secondary Oxidation Products of Geometric Isomers of Conjugated Linoleic Acid Methyl Esters: Structures in Solution and Revision of NMR Assignments.

Detailed DFT studies of 1H and 13C NMR chemical shifts of hydroxy secondary oxidation products of various geometric isomers of conjugated linolenic acids methyl esters are presented. Several low energy conformers were identified for model compounds of the central dienenol OH moiety, which were found to be practically independent on the various functionals and basis sets used. This greatly facilitated the minimization process of the geometric isomers of conjugated linolenic acids methyl esters. Several regularities of the literature experimental 1H and 13C chemical shifts were reproduced very accurately with the computational chemical shifts of the Gibbs low energy DFT optimized conformers, after a Boltzmann analysis. δ(13C) and δ(1H) of the methine CH-OH group are highly diagnostic for the trans/trans and cis/trans geometric isomerism of the adjacent double bond. δ(13C) of the -CH2- group adjacent to the terminal double bond of the conjugated system strongly depend on the cis/trans geometric isomerism of this bond and, thus, could be of importance in structural analysis. Ambiguities in the reported literature resonance assignments of olefinic carbons had been resolved. Computational δ(1H) and δ(13C) can be utilized for the identification of geometric isomerism and structural and conformational elucidation of hydroxy derivatives of conjugated linoleic acids and their ester derivatives.

Conformational Analysis of Swallowtail Motifs in Porphyrins.

Aqueous solubilization of porphyrins, often accomplished with appended polar aryl groups, can also be achieved with symmetrically branched alkyl (i.e., swallowtail) groups terminated with polar moieties. Here, carboxylic acids are employed as termini (versus prior phosphono- or phosphoester termini) in designs of trans-AB-porphyrins bearing a single swallowtail group (A) or trans-A2-porphyrins bearing two swallowtail groups. Variable-temperature 1H NMR studies (-60 to 97 °C) revealed that the 4-heptanedioic acid group at the meso-position of the free base porphyrin rotates with rate constant 5 s-1 (310 K) and Arrhenius energy barrier Ea = 11.5 kcal/mol, whereas an isopropyl group undergoes rotation ∼1000-times faster (k = 5770 s-1). The interconversion is sufficiently fast that conformational diastereomers, as when two such swallowtail groups are present in a trans-A2-porphyrin, would not be isolable at room temperature (Class I atropisomers). DFT calculations (4 porphyrins containing the isopropyl or 4-heptanedioic acid groups) showed that the lowest energy conformer contains the swallowtail C-H unit in the plane of the porphyrin. The presence of one or two 4-heptanedioic acid moieties imparted solubility of the porphyrin in phosphate-buffered saline (PBS). The results suggest applications in the life sciences where compact, aqueous-soluble porphyrins are desired.

Favorable Symmetric Structures of Radiopharmaceutically Important Neutral Cyclen-Based Ligands

Cyclen-based ligands are prominent tools for transferring radioisotopes through the human body. A crucial criterion is the stability of their complexes, which is partly determined by the stabilization of the free ligand in solution. For the assessment of the later property, the favored conformation(s) in the solution must be known. In the present study, the conformational space of four neutral cyclen-based ligands was elucidated by a multi-step procedure: the survey of the conformational space using molecular mechanics (MM) was followed by Density Functional Theory (DFT) calculations on the low-energy conformers and evaluation of the solvent effects. The results revealed several low-energy conformers in aqueous solution. In terms of electronic energies, a significant preference of symmetric structures (C4 or C2—similar to the ligand arrangements in their metal complexes) was obtained. The thermal contributions to the Gibbs free energy (mainly the vibrational ones) tend to decrease this preference by several kJ/mol against non-symmetric structures. Nonetheless, the advantage of compact symmetric structures was confirmed in all the four studied cases.

In Vivo and Computational Studies on Sitagliptin's Neuroprotective Role in Type 2 Diabetes Mellitus: Implications for Alzheimer's Disease.

Diabetes mellitus (DM), a widespread endocrine disorder characterized by chronic hyperglycemia, can cause nerve damage and increase the risk of neurodegenerative diseases such as Alzheimer's disease (AD). Effective blood glucose management is essential, and sitagliptin (SITG), a dipeptidyl peptidase-4 (DPP-4) inhibitor, may offer neuroprotective benefits in type 2 diabetes mellitus (T2DM). T2DM was induced in rats using nicotinamide (NICO) and streptozotocin (STZ), and biomarkers of AD and DM-linked enzymes, inflammation, oxidative stress, and apoptosis were evaluated in the brain. Computational studies supported the in vivo findings. SITG significantly reduced the brain enzyme levels of acetylcholinesterase (AChE), beta-secretase-1 (BACE-1), DPP-4, and glycogen synthase kinase-3β (GSK-3β) in T2DM-induced rats. It also reduced inflammation by lowering cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB). Additionally, SITG improved oxidative stress markers by reducing malondialdehyde (MDA) and enhancing glutathione (GSH). It increased anti-apoptotic B-cell lymphoma protein-2 (Bcl-2) while reducing pro-apoptotic markers such as Bcl-2-associated X (BAX) and Caspace-3. SITG also lowered blood glucose levels and improved plasma insulin levels. To explore potential molecular level mechanisms, docking was performed on AChE, COX-2, GSK-3β, BACE-1, and Caspace-3. The potential binding affinity of SITG for the above-mentioned target enzymes were 10.8, 8.0, 9.7, 7.7, and 7.9 kcal/mol, respectively, comparable to co-crystallized ligands. Further binding mode analysis of the lowest energy conformation revealed interactions with the critical residues. These findings highlight SITG's neuroprotective molecular targets in T2DM-associated neurodegeneration and its potential as a therapeutic approach for AD, warranting further clinical investigations.

Vibrational spectroscopic characterization, quantum chemical, molecular docking and molecular dynamics investigations of cyclo(L-phenylalanyl-L-proline), an anticancer agent

The molecular structure and spectral properties of cyclo(L-Phenylalanyl-L-Proline) dipeptide, which has several biological activities, were investigated. Firstly, conformational preference of the cyclo(L-Phenylalanyl-L-Proline) was searched and obtained lowest energy conformer of the cyclic dipeptide was then optimized using Density Functional Theory with wb97xd/6-311++G(d,p) level of theory. A detailed vibrational spectral analysis has been carried out and assignments of the fundamental modes have been proposed. The experimental vibrational wavenumbers of the investigated compound display good agreement with the computed values. The Frontier Molecular Orbitals, Molecular Electrostatic Potential and electronic transitions of the investigated compound were discussed. In addition, the 1H and 13C NMR chemical shifts of the cyclic dipeptide were calculated and the results were compared with the experimental values. Also, to evaluate the anticancer potential, molecular docking studies of cyclo(L-Phenylalanyl-L-Proline) within the ATP-binding sites of both wild type (EGFRWT; ID: 4HJO) and mutant (EGFRT790M; ID: 3W2O) Epidermal Growth Factor Receptor were performed. The results indicated that cyclo(Phe-Pro) has high binding affinities toward both EGFRWT (−6.6 kcal/mol) and EGFRT790M (−7.7 kcal/mol) receptors, thus, has good anticancer activity and also has potential to overcome drug resistance in therapy. Molecular dynamics simulations on cyclo(L-Phenylalanyl-L-Proline)-wild type complex were conducted through a 50-nanosecond timed to investigate the ligand-receptor interactions in more detail, and to determine the binding free energy accurately. The binding free energy of the cyclo(L-Phenylalanyl-L-Proline)-wild type complex was calculated to be −27.18 kcal/mol.

Structure of a Cyclic Peptide as an Inhibitor of Mycobacterium tuberculosis Transcription: NMR and Molecular Dynamics Simulations.

A novel antitubercular cyclic peptide, Cyclo(1,6)-Ac-CLYHFC-NH2, was designed to bind at the rifampicin (RIF) binding site on the RNA polymerase (RNAP) of Mycobacterium tuberculosis (MTB). This peptide inhibits RNA elongation in the MTB transcription initiation assay in the nanomolar range, which can halt the MTB transcription initiation complex, similar to RIF. Therefore, determining the solution conformation of this peptide is useful in improving the peptide's binding affinity to the RNAP. Here, the solution structure of Cyclo(1,6)-Ac-CLYHFC-NH2 was determined by two-dimensional (2D) NMR experiments and NMR-restrained molecular dynamic (MD) simulations. All protons of Cyclo(1,6)-Ac-CLYHFC-NH2 were assigned using TOCSY and NOE NMR spectroscopy. The NOE cross-peak intensities were used to calculate interproton distances within the peptide. The JNH-HCα coupling constants were used to determine the possible Phi angles within the peptide. The interproton distances and calculated Phi angles from NMR were used in NMR-restrained MD simulations. The NOE spectra showed NH-to-NH cross-peaks at Leu2-to-Tyr3 and Tyr3-to-His4, indicating a βI-turn formation at the Cys1-Leu2-Tyr3-His4 sequence. The NMR-restrained MD simulations showed several low-energy conformations that were congruent with the NMR data. Finally, the conformation of this peptide will be used to design derivatives that can better inhibit RNAP activity.

Enantioselective Complexation of Protonated Tyrosine by a Chiral Crown-ether: The Nature of the Hydrogen Bonds Makes the Difference.

The complexes formed between (18-crown-6)-tetracarboxylic acid, denoted as 18C6TA, and the two enantiomers of protonated tyrosine, L- and D-Tyr, are studied in a cryogenic ion trap by combining mass spectrometry, laser spectroscopy, and DFT calculations. Both UV and IR photodissociation spectra indicate the formation of multiple isomers for each complex, some of them interconverting upon IR irradiation. Conformer-selective vibrational spectroscopy reveals that all structures involve an internally hydrogen-bonded folded structure of the crown ether. The complexes formed with L-Tyr involve two NH…O interactions with the ether oxygen atoms, accompanied by two hydrogen bonds to the crown ether carboxylic function, one from the NH group and the other from the COOH group of tyrosine. The complexes formed with D-Tyr show more conformational mobility: two out of the three lowest energy conformers observed are tripodal, with three NH…O interactions between the amino acid ammonium and the crown ether oxygens. An additional conformer shows only one NH…O interaction, but has two interactions involving one of the cavity COOH moieties, one with the NH and one with the phenol OH. The increased calculated stability of the complex made from (-) 18C6TA and L-Tyr parallels its higher abundance in the mass spectrum of an isotopically labelled racemic mixture.

Significant Chiral Asymmetry Observed in Neutral Amino Acid Ultraviolet Photolysis.

The origin of homochirality in biological organisms remains an open question. Some suggest that its origin might be extraterrestrial, specifically due to the exposure of chiral molecules to circularly polarized photons in interstellar space, which could cause an initial population imbalance leading to the homochirality observed today. However, this extraterrestrial hypothesis has not been widely accepted, largely due to the belief that molecular optical rotatory dispersion is too insignificant to create the substantial imbalance required for homochirality. Here we report experimental evidence that specific conformers of neutral amino acids exhibit significant asymmetry in the chiral destroying dissociation rate induced by circularly polarized photons. The observed anisotropy factor for the lowest energy conformer of leucine was remarkably large, reaching 0.1─a factor of 13 times larger than observed for zwitterionic leucine in solid films, and nearly 40 times greater than the anisotropy reported in the electronic absorption spectrum of gas-phase leucine ensembles at room temperature. This significant finding indicates that even if reported anisotropy values in the electronic absorption spectrum are low, the dissociation asymmetry of certain conformers can still be substantial. An anisotropy factor of 0.1 could result in an initial enantiomeric excess exceeding 10%, even with a 90% extent of reaction. This discovery suggests that asymmetric photodissociation of amino acids may have been a crucial factor in the emergence of biological homochirality.

The adsorption of drugs on nanoplastics has severe biological impact

Micro- and nanoplastics can interact with various biologically active compounds forming aggregates of which the effects have yet to be understood. To this end, it is vital to characterize these aggregates of key compounds and micro- and nanoplastics. In this study, we examined the adsorption of the antibiotic tetracycline on four different nanoplastics, made of polyethylene (PE), polypropylene (PP), polystyrene (PS), and nylon 6,6 (N66) through chemical computation. Two separate approaches were employed to generate relevant conformations of the tetracycline-plastic complexes. In the first approach, we folded the plastic particle from individual polymer chains in the presence of the drug through multiple separate simulated annealing setups. In the second, more biased, approach, the neat plastic was pre-folded through simulated annealing, and the drug was placed at its surface in multiple orientations. The former approach was clearly superior to the other, obtaining lower energy conformations even with the antibiotic buried inside the plastic particle. Quantum chemical calculations on the structures revealed that the adsorption energies show a trend of decreasing affinity to the drug in the order of N66> PS> PP> PE. In vitro experiments on tetracycline-sensitive cell lines demonstrated that, in qualitative agreement with the calculations, the biological activity of tetracycline drops significantly in the presence of PS particles. Preliminary molecular dynamics simulations on two selected aggregates with each plastic served as first stability test of the aggregates under influence of temperature and in water. We found that all the selected cases persisted in water indicating that the aggregates may be stable also in more realistic environments. In summary, our data show that the interaction of micro- and nanoplastics with drugs can alter drug absorption, facilitate drug transport to new locations, and increase local antibiotic concentrations, potentially attenuating antibiotic effect and at the same time promoting antibiotic resistance.

Photochemical and Collision-Induced Cross-Linking in Stereochemically Distinct Scaffolds of Peptides and Nitrile Imines in Gas-Phase Ions.

Intramolecular cross-linking between peptides and nitrile-imine intermediates was studied in stereochemically distinct conjugates in which the reacting components were mounted on cis-1,2-cyclohexane and trans-1,4-cyclohexane scaffolds that we call 1,2-s-peptides and 1,4-s-peptides, respectively. The nitrile-imine intermediates were generated by N2 loss from 2,5-diaryltetrazole tags upon UV-photodissociation at 213 and 250 nm or by collision-induced dissociation, and further interrogated by CID and UVPD-MS3. Peptide fragment ion series originating from linear structures and macrocyclic cross-links were distinguished and used to quantify the cross-linking yields. The yields in MS2 varied between 27% for AAAG conjugates to 78% for GAAAK conjugates, depending on the peptide sequence. The CID-MS3 yields were in a 57-97% range, depending on the peptide sequence. Structures of 1,2-s-peptide and 1,4-s-peptide ions as well as several of their nitrile-imine intermediates and cross-links were investigated by high-resolution cyclic ion mobility in combination with Born-Oppenheimer molecular dynamics and density functional theory calculations. Matches between the experimental and calculated collision cross sections and ion relative Gibbs energies were used to assign peptide structures. Peptide conjugates C-terminated with Gly and Lys residues underwent cross-linking by the carboxyl group, as established by MS3 sequencing and corroborated by carboxyl blocking experiments that lowered the cross-linking yields. Peptide conjugates C-terminated with Arg also cross-linked via the side-chain guanidine group. A notable feature of the 1,4-s-peptide ions was the participation of low-energy twist-boat cyclohexane conformers that was enforced by strong hydrogen bonds between the peptide and nitrile imine.

Electronic Structures and Spectra of Donor-Acceptor Conjugated Oligomers.

Narrow band gap donor-acceptor conjugated polymers present excellent paradigms in photonics and optoelectronics due to their chemical tunability, correlated electronic structures, and tunable open-shell electronic configurations. However, rational design for enhancing the properties of these molecular systems remains challenging. In this study, we employed density functional theory (DFT) calculations to investigate prototypical narrow band gap donor-acceptor conjugated oligomers, consisting of alternating cyclopentadithiophene (CPDT) donors paired with benzothiadiazole (BT), benzoselenadiazole (BSe), benzobisthiadiazole (BBT), and thiadiazoloquinoxaline (TQ) acceptors. Analyses of structures, singlet-triplet gaps, and absorption spectra of oligomers with up to ten repeat units have shown that when incorporating the BT, BSe, and TQ acceptors, the backbone curvature resulted in spiral structures that were energetically favored over their linear counterparts, causing differences in the calculated circular dichroism spectra. Oligomers with BBT-based acceptors preferred, however, a linear geometry, consistent with an open-shell electronic structure. Calculated singlet-triplet splittings demonstrated the importance of long chains and specific structures for consistency with the experiment, while effects of the solvent were also quantified. Based on the predicted low-energy conformations, one-photon absorption spectra for the considered oligomers have shown that using the Tamm-Dancoff approximation within time-dependent DFT for the large systems offers good agreement with the first absorption maxima in measured experimental spectra, thus validating the method for large donor-acceptor oligomers. Natural transition orbital analyses provided insights into the excited-state characteristics. Two-photon absorption maxima were accurately predicted, but the cross-sections were overestimated or underestimated, as dependent on the level of theory employed, to be addressed in future work.

Does Aromaticity Play a Role in Electronic and Structural Properties of YBn (n=2-14) Clusters?

Nanoclusters exhibit electronic, optical, and magnetic properties that differ significantly from those of extended and molecular systems with comparable stoichiometries. In this work, we examined the structural, energetic, and electronic characteristics of yttrium-doped boron clusters (YBn, where n ranges from 2 to 14) with the aid of robust wavefunction analysis tools. Special emphasis is placed on the elucidation of the potential aromatic character exhibited by the resultant molecules and how it can affect their chemical bonding and stability. Our results revealed that the YBn stability is governed by the maximization of the ionic Y-B interactions. This circumstance is evidenced from the lowest-energy conformations, which manifest as half-sandwich structures wherein the majority of boron atoms are bonded to yttrium. The stabilization of such chemical contacts comes at the expense of a notorious depletion of the Y local electron density, crystallizing in a considerable ionic character, close to Y2++ . Such a prominent charge transfer is coupled to the enhancement of the electron delocalization within the Bn lattice, resulting in quite remarkable local and global aromatic characters. Altogether, this study shows how the toolkit of real space chemical bonding descriptors can offer valuable insights into the structural and electronic properties, along with the chemical bonding, of YBn clusters, contributing to a more comprehensive understanding of their behavior.

Structural dissection of the CMP-pseudaminic acid synthetase, PseF

Pseudaminic acid is a non-mammalian sugar found in the surface glycoconjugates of many bacteria, including several human pathogens, and is a virulence factor thought to facilitate immune evasion. The final step in the biosynthesis of the nucleotide activated form of the sugar, CMP-Pse5Ac7Ac is performed by a CMP-Pse5Ac7Ac synthetase (PseF). Here we present the biochemical and structural characterization of PseF from Aeromonas caviae (AcPseF), with AcPseF displaying metal-dependent activity over a broad pH and temperature range. Upon binding to CMP-Pse5Ac7Ac, AcPseF undergoes dynamic movements akin to other CMP-ulosonic acid synthetases. The enzyme clearly discriminates Pse5Ac7Ac from other ulosonic acids, through active site interactions with side-chain functional groups and by positioning the molecule in a hydrophobic pocket. Finally, we show that AcPseF binds the CMP-Pse5Ac7Ac side chain in the lowest energy conformation, a trend that we observed in the structures of other enzymes of this class.

A novel application of hydrophilic interaction liquid chromatography for the identification of compounds with intramolecular hydrogen bonds

The incorporation of intramolecular hydrogen bonds (IMHB) into small molecules constitutes an interesting optimization strategy to afford potential drug candidates with enhanced solubility as well as permeability and consequently improved bioavailability (if metabolic stability is high). Common methods to assess IMHB rely on spectroscopic or diffraction techniques, which, however, have limited throughput when screening for hit compounds in early phases of drug discovery. Inspired by literature findings using supercritical fluid chromatography (SFC) as an indirect method for IMHB identification in a screening context, we aimed at developing a secondary chromatographic methodology taking advantage of commonly used HPLC-MS instrumentation. In this work, we explored hydrophilic interaction liquid chromatography (HILIC) and developed a method for discriminating compounds based on their hydrogen bonding features. By quantifying retention of different matched molecular pairs (MMP) and using information about their low energy conformations from quantum-mechanical calculations, we defined a hydrogen bonding-driven adsorption (kads) chromatographic parameter to assess a compound’s propensity to forming IMHB. In addition to the MMP analysis, we found that the kads parameter allows for the differentiation of analytes forming IMHB regardless of the comparison with control compounds.

Identification of novel brain penetrant GSK-3β inhibitors toward Alzheimer’s disease therapy by virtual screening, molecular docking, dynamic simulation, and MMPBSA analysis

One of the significant therapeutic targets for Alzheimer’s disease (AD) is Glycogen Synthase Kinase-3β (GSK-3β). Inhibition of GSK-3β can prevent hyperphosphorylation of tau, and thus prevent formation and accumulation of neurofibrillary tangles and neuropil threads that block intracellular transport, trigger unfolded protein response, and increase oxidative stress, cumulatively leading to neurodegeneration. In this study, we have performed structure-based virtual screening of two small-molecule libraries from ChemDiv CNS databases using AutoDock Vina to identify hit molecules based on their binding affinities compared to that of an established GSK-3β inhibitor, indirubin-3’-monoxime (IMO). Pharmacoinformatic screening on SwissADME and pkCSM servers enabled identification of lead molecules with favorable pharmacoinformatic properties for drug likeliness, including blood brain barrier (BBB) permeability. Further, molecular dynamic simulations identified six candidate lead molecules that show stable complex formation with GSK-3β in dynamic state under physiological conditions. Principal component analysis of the dynamic state was used to plot Free Energy Landscapes (FELs) of GSK-3β-ligand complexes. STRIDE secondary structure analysis of the lowest energy conformations identified from FEL plots, and binding free energy calculations by Molecular Mechanics Poisson-Boltzmann Surface Area ((ΔGbind )MM-PBSA) of the simulation trajectories led to the identification of two ligands as potential lead molecules having favorable free energy landscape profiles as well as significantly lower (ΔGbind )MM-PBSA in dynamic state compared to that of reference inhibitor IMO. Hence, this study identifies two novel brain penetrant GSK-3β inhibitors that are likely to have therapeutic potential against Alzheimer’s disease.

Infrared Spectrum of the Adduct 2-Chloro-2-hydroperoxybut-3-ene [(C2H3)CCl(CH3)OOH] of the Reaction between the Criegee Intermediate Methyl Vinyl Ketone Oxide [C2H3C(CH3)OO] and HCl.

Methyl vinyl ketone oxide (MVKO, C2H3C(CH3)OO) is an important Criegee intermediate produced from ozonolysis of isoprene, which is the most abundant nonmethane hydrocarbon emitted into the atmosphere. Reactions between Criegee intermediate and hydrogen chloride (HCl) are important because of their large rate coefficients. In this work, we photolyzed a mixture of (Z)-(CH2I)HC═C(CH3)I/HCl/O2 at 248 nm to produce MVKO to carry out the reaction MVKO + HCl and recorded infrared spectra of transient species with a step-scan Fourier-transform infrared absorption spectrometer. Eleven bands near 1415, 1381, 1350, 1249, 1178, 1118, 1103, 1065, 978, 931, and 895 cm-1 were observed and assigned to the hydrogen-transferred adduct (C2H3)CCl(CH3)OOH (2-chloro-2-hydroperoxybut-3-ene, CHPB) according to the predicted IR spectrum using the B3LYP/aug-cc-pVTZ method; the conformation could not be definitively determined. According to calculations, most low-energy conformers can interconvert, and the most stable conformers anti-trans-CHPB and syn-trans-CHPB might have the major contributions. Four bands near 1423, 1360, 1220, and 1080 cm-1 were observed and tentatively assigned to the OH-decomposition products (C2H3)CCl(CH3)O (1-chloro-1-methyl-2-propenyloxy, CMP); both trans-CMP and cis-CMP might contribute. Unlike in the case of CH2OO + HCl and CH3CHOO + HCl, in which secondary reactions of the OH-decomposition products reacted readily with O2 to produce the dehydrated products HC(O)Cl and CH3C(O)Cl, respectively, the secondary reaction of CMP with O2 was not observed because there is no feasible H atom in CMP for O2 to abstract.