Low-energy Conformations Research Articles

Making Use of Averaging Methods in MODELLER for Protein Structure Prediction.

Recent advances in protein structure prediction, driven by AlphaFold 2 and machine learning, demonstrate proficiency in static structures but encounter challenges in capturing essential dynamic features crucial for understanding biological function. In this context, homology-based modeling emerges as a cost-effective and computationally efficient alternative. The MODELLER (version 10.5, accessed on 30 November 2023) algorithm can be harnessed for this purpose since it computes intermediate models during simulated annealing, enabling the exploration of attainable configurational states and energies while minimizing its objective function. There have been a few attempts to date to improve the models generated by its algorithm, and in particular, there is no literature regarding the implementation of an averaging procedure involving the intermediate models in the MODELLER algorithm. In this study, we examined MODELLER's output using 225 target-template pairs, extracting the best representatives of intermediate models. Applying an averaging procedure to the selected intermediate structures based on statistical potentials, we aimed to determine: (1) whether averaging improves the quality of structural models during the building phase; (2) if ranking by statistical potentials reliably selects the best models, leading to improved final model quality; (3) whether using a single template versus multiple templates affects the averaging approach; (4) whether the "ensemble" nature of the MODELLER building phase can be harnessed to capture low-energy conformations in holo structures modeling. Our findings indicate that while improvements typically fall short of a few decimal points in the model evaluation metric, a notable fraction of configurations exhibit slightly higher similarity to the native structure than MODELLER's proposed final model. The averaging-building procedure proves particularly beneficial in (1) regions of low sequence identity between the target and template(s), the most challenging aspect of homology modeling; (2) holo protein conformations generation, an area in which MODELLER and related tools usually fall short of the expected performance.

Exploring the conformational landscape, hydrogen bonding, and internal dynamics in the diallyl ether and diallyl sulfide monohydrates.

The conformational spaces of the diallyl ether (DAE) and diallyl sulfide (DAS) monohydrates were explored using rotational spectroscopy from 6 to 19GHz. Calculations at the B3LYP-D3(BJ)/aug-cc-pVTZ level suggested significant differences in their conformational behavior, with DAE-w exhibiting 22 unique conformers and DAS-w featuring three stable structures within 6 kJ mol-1. However, only transitions from the lowest energy conformer of each were experimentally observed. Spectral analysis confirmed that binding with water does not alter the conformational preference for the lowest energy structure of the monomers, but it does influence the relative stabilities of all other conformers, particularly in the case of DAE. Non-covalent interaction and quantum theory of atoms in molecules analyses showed that the observed conformer for each complex is stabilized by two intermolecular hydrogen bonds (HBs), where water primarily interacts with the central oxygen or sulfur atom of the diallyl compounds, along with secondary interactions involving the allyl groups. The nature of these interactions was further elucidated using symmetry-adapted perturbation theory, which suggests that the primary HB interaction with S in DAS is weaker and more dispersive in nature compared to the primary HB in DAE. This supports the experimental observation of a tunneling splitting exclusively in the rotational spectrum of DAS-w, as the weaker contact allows water to undergo internal motions within the complex, as shown based on calculated transition state structures for possible tunneling pathways.

Mechanism of Ligand Binding to Theophylline RNA Aptamer.

Studying RNA-ligand interactions and quantifying their binding thermodynamics and kinetics are of particular relevance in the field of drug discovery. Here, we combined biochemical binding assays and accelerated molecular simulations to investigate ligand binding and dissociation in RNA using the theophylline-binding RNA as a model system. All-atom simulations using a Ligand Gaussian accelerated Molecular Dynamics method (LiGaMD) have captured repetitive binding and dissociation of theophylline and caffeine to RNA. Theophylline's binding free energy and kinetic rate constants align with our experimental data, while caffeine's binding affinity is over 10,000 times weaker, and its kinetics could not be determined. LiGaMD simulations allowed us to identify distinct low-energy conformations and multiple ligand binding pathways to RNA. Simulations revealed a "conformational selection" mechanism for ligand binding to the flexible RNA aptamer, which provides important mechanistic insights into ligand binding to the theophylline-binding model. Our findings suggest that compound docking using a structural ensemble of representative RNA conformations would be necessary for structure-based drug design of flexible RNA.

Exploring the impact of alignment media on RDC analysis of phosphorus-containing compounds: a molecular docking approach.

Residual dipolar couplings (RDCs) are employed in NMR analysis when conventional methods, such as J-couplings and nuclear Overhauser effects (NOEs) fail. Low-energy (optimized) conformers are often used as input structures in RDC analysis programs. However, these low-energy structures do not necessarily resemble conformations found in anisotropic environments due to interactions with the alignment medium, especially if the analyte molecules are flexible. Considering interactions with alignment media in RDC analysis, we developed and evaluated a molecular docking-based approach to generate more accurate conformer ensembles for compounds in the presence of the poly-γ-benzyl-L-glutamate alignment medium. We designed chiral phosphorus-containing compounds that enabled us to utilize 31P NMR parameters for the stereochemical analysis. Using P3D/PALES software to evaluate diastereomer discrimination, we found that our conformer ensembles outperform moderately the standard, low-energy conformers in RDC analysis. To further improve our results, we (i) averaged the experimental values of the molecular docking-based conformers by applying the Boltzmann distribution and (ii) optimized the structures through normal mode relaxation, thereby enhancing the Pearson correlation factor R and even diastereomer discrimination in some cases. Nevertheless, we presume that significant differences between J-couplings in isotropic and in anisotropic environments may preclude RDC measurements for flexible molecules. Therefore, generating conformer ensembles based on molecular docking enhances RDC analysis for mildly flexible systems while flexible molecules may require applying more advanced approaches, in particular approaches including dynamical effects.

Exploration of carvacrol aggregation by laser spectroscopy.

Carvacrol is an aromatic monoterpenoid found in thyme oil. Due to its implications for human health, it is important to elucidate its structure and its intramolecular interactions. We have characterised the carvacrol monomer, its complex with water, its dimer, and even its trimer in a supersonic expansion using mass-resolved laser spectroscopy techniques complemented by quantum-chemical computations. The resonance-enhanced multiphoton ionisation spectrum of the monomer features several transitions, which were assigned to the same conformer, confirmed by ion-dip infrared spectroscopy. However, a conclusive assignment of the infrared bands to one of the four conformations of carvacrol remains elusive. The experimental spectra for the monohydrated, the homodimer, and the homotrimer point to the detection of the lowest energy isomer in each case. Their structures are governed by a balance of intramolecular interactions, specifically hydrogen bonding and dispersion forces. Comparison with other similar systems demonstrates that dispersion interactions are key to the stabilisation of the aggregates, being present in all the structures. However, the hydrogen bonding is the dominant force as observed in the lowest-energy conformations.

Phase-dependent polymerization isomerism in the coordination complexes of a flexible bis(β-diketonato) ligand.

First prepared in the late 70s, the pro-ligand 1,3-bis(3,5-dioxo-1-hexyl)benzene (H2bdhb) contains two acetoacetyl terminations linked to a central 1,3-phenylene unit through dimethylene bridges. Since each termination can be either in diketonic or keto-enolic form, in organic solution it exists as a mixture of three spectroscopically resolvable tautomers. In the presence of pyridine, Co2+ and the bdhb2- anion form a crystalline dimeric compound with formula [Co2(bdhb)2(py)4] (2) and a Co⋯Co separation of more than 11 Å. Complex 2 contains two pseudo-octahedrally coordinated and non-interacting high-spin cobalt(II) ions (S = 3/2) displaying a large easy-plane anisotropy (D ∼ 70 cm-1), as consistently indicated by magnetic measurements, X-band EPR spectra, and complete active space self-consistent field/N-electron valence state perturbation theory (CASSCF/NEVPT2) calculations. At cryogenic temperatures (T < 7 K) and in an applied static magnetic field, the compound shows detectably slow magnetic relaxation, which occurs through direct and Raman mechanisms. Combined mass spectrometry, UV-Vis, and 1H/2H NMR data, including an isotopic labelling experiment and a determination of molecular weight by diffusion ordered spectroscopy (DOSY), show that 2 rearranges to monomeric high-spin [Co(bdhb)(py)x] species (x = 0, 1, or 2) in organic solution (CH2Cl2, THF) with concomitant partial dissociation of the py ligands. The X-band EPR spectra in a frozen CH2Cl2/toluene matrix concurrently suggest a significant alteration of the coordination environment upon dissolution. These observations are fairly well reproduced by density functional theory (DFT) and CASSCF/NEVPT2 calculations on the lowest Gibbs free energy conformers of each species, as provided by an extensive conformational search based on meta-dynamics simulations and semiempirical tight-binding methods. After the vanadyl analogue, compound 2 provides the second example of polymerization isomerism in the 1 : 1 adducts of bdhb2- with divalent metal ions.

A first-principles exploration of the conformational space of sodiated di-saccharides assisted by semi-empirical methods and neural network potentials.

Previous exploration of the conformational space of sodiated mono-saccharides using a random search algorithm leads to ∼103 structurally distinct conformers covering an energy range of ∼150 kJ mol-1. Thus, it is reasonable to expect that the number of distinct conformers for a given disaccharide would be on the order of 106. Efficient identification of distinct conformers at the first-principles level has been demonstrated with the assistance of neural network potential (NNP) with an accuracy of ∼1 kJ mol-1 compared to DFT. Leveraging a local minima database of neutral and sodiated glucose (Glc), we develop algorithms to systematically explore the conformation landscape of 19 Glc-based sodiated disaccharides. To accelerate the exploration, the NNP method is implemented. The NNP achieves an accuracy of ∼2.3 kJ mol-1 compared to DFT, offering a comparable quality to that of DFT. Through a multi-model approach integrating DFTB3, NNP and DFT, we can rapidly locate low-energy disaccharide conformers at the first-principles level. The methodology we show here can be used to efficiently explore the potential energy landscape of any di-saccharides when first-principles accuracy is required.

Automated exploration of the conformational degrees of freedom along reaction profiles - driving a FASTCAR.

This publication aims at presenting a Python-based workflow designed to enable a fully automatised and exhaustive exploration of the conformational degrees of freedom within the calculation of reaction paths in molecular systems. The proposed strategy focuses on effectively representing the lowest energy conformers for intricate, highly rotatable, and non-intuitive transition states, reagents and products, using existing computational tools. The article presents a workflow that is demonstrated through the application of five chemical reactions, chosen to be representative of the diversity and complexity of actual experimental studies, and which often prove to be challenging to study "by hand". The proposed methodology is expected to be of a great help in the modelling of state-of-the art organic chemistry reactions, whose complexity is ever increasing.

Exploration of SAM-I riboswitch inhibitors: In-Silico discovery of ligands to a new target employing multistage CADD approaches

Targeting riboswitches, regulatory elements responsible for the expression of essential genes, is taking central stage in the new era of antibacterial medications discovery due to the emergence of antibiotic resistance. The S-Adenosyl methionine-I (SAM-I) riboswitch works through transcription termination in a negative feedback manner modulated by the natural ligand SAM. SAM-I riboswitch is specific to bacteria and found mainly in gram-positive bacteria such as Bacillus anthracis. Analyzing the interactions of the co-crystallized structure of SAM-I riboswitch aptamer with its native ligand SAM clarified the needed chemical structural features to achieve binding. Acknowledging those features, structure-based and ligand-based pharmacophore models were built for filtration use in screening the OTAVA Chemical library and the Pubchem database. For further filtration enhancement, the physicochemical properties of SAM were used as a second filtration criterion. Compounds obtained as output from previous steps were energy minimized, and the lowest energy conformer structures were docked to SAM-I using MOE, v.2019.01. S-score and ligand interactions were used to assess the best hits. This yielded eight promising compounds to which molecular dynamics (MD) simulations with SAM-I aptamer were applied using GROMACS 2020.3 package affirming stable binding interactions and binding energetics similar to SAM. Moreover, pharmacokinetic and drug-like properties of those eight hits were assessed using SWISS-ADME. According to the combined computational methods and PK/Tox assessment, compound 20 was the most promising and thus can be considered a lead for future evaluation and optimization as a candidate new antibacterial agent targeting a new biomolecule eliciting a new mechanism of action.

Searching low-energy conformers of neutral and protonated di-, tri-, and tetra-glycine using first-principles accuracy assisted by the use of neural network potentials.

In the last ten years, combinations of state-of-the-art gas-phase spectroscopies and quantum chemistry calculations have suggested several intuitive trends in the structure of small polypeptides that may not hold true. For example, the preference for the cis form of the peptide bond and multiple protonated sites was proposed by comparing experimental spectra with low-energy minima obtained from limited structural sampling using various density functional theory methods. For understanding the structures of polypeptides, extensive sampling of their configurational space with high-accuracy computational methods is required. In this work, we demonstrated the use of deep-learning neural network potential (DL-NNP) to assist in exploring the structure and energy landscape of di-, tri-, and tetra-glycine with the accuracy of high-level quantum chemistry methods, and low-energy conformers of small polypeptides can be efficiently located. We hope that the structures of these polypeptides we found and our preliminary analysis will stimulate further experimental investigations.

Asymmetric cycloadditions, diels-alder and cyclopropanation transformations, with (S)-Benzyl N-2-trifluoroacetamidoacrylyl oxazolidinone

Asymmetric transformations to access derivatives of amino acids offer useful approaches to intermediates for target directed synthesis and for medicinal agents. Two new selective transformations are reported using S-benzyl acetamidoacrylate oxazolidinone 1 include Diels-Alder [4 + 2]-cycloaddition with cyclopentadiene and cyclopropanation via aryl tosyl hydrazones. Use of titanium (IV) chloride at room temperature (3 h) with 1 and cyclopentadiene generated the norbornene amino acyloxazolidinone product 6 (82 %) with high dienophile facial preference and 2:1 exo over endo selectivity. Cyclopropanation of 1 with phenyl tosyl hydrazone under phase transfer conditions at 60 °C gave product 8 (71 %) with 3:1 E to Z selectivity. Observed selectivity is consistent with proposed transition states of metal chelates of 1 in low energy conformation.

Mechanistic Insights into Peptide Binding and Deactivation of an Adhesion G Protein-Coupled Receptor.

Adhesion G protein-coupled receptors (ADGRGs) play critical roles in the reproductive, neurological, cardiovascular, and endocrine systems. In particular, ADGRG2 plays a significant role in Ewing sarcoma cell proliferation, parathyroid cell function, and male fertility. In 2022, a cryo-EM structure was reported for the active ADGRG2 bound by an optimized peptide agonist IP15 and the Gs protein. The IP15 peptide agonist was also modified to antagonists 4PH-E and 4PH-D with mutations of the 4PH residue to Glu and Asp, respectively. However, experimental structures of inactive antagonist-bound ADGRs remain to be resolved, and the activation mechanism of ADGRs such as ADGRG2 is poorly understood. Here, we applied Gaussian accelerated molecular dynamics (GaMD) simulations to probe conformational dynamics of the agonist- and antagonist-bound ADGRG2. By performing GaMD simulations, we were able to identify important low-energy conformations of ADGRG2 in the active, intermediate, and inactive states, as well as explore the binding conformations of each peptide. Moreover, our simulations revealed critical peptide-receptor residue interactions during the deactivation of ADGRG2. In conclusion, through GaMD simulations, we uncovered mechanistic insights into peptide (agonist and antagonist) binding and deactivation of the ADGRG2. These findings will potentially facilitate rational design of new peptide modulators of ADGRG2 and other ADGRs.

Applying atomistic neural networks to bias conformer ensembles towards bioactive-like conformations

Identifying bioactive conformations of small molecules is an essential process for virtual screening applications relying on three-dimensional structure such as molecular docking. For most small molecules, conformer generators retrieve at least one bioactive-like conformation, with an atomic root-mean-square deviation (ARMSD) lower than 1 Å, among the set of low-energy conformers generated. However, there is currently no general method to prioritise these likely target-bound conformations in the ensemble. In this work, we trained atomistic neural networks (AtNNs) on 3D information of generated conformers of a curated subset of PDBbind ligands to predict the ARMSD to their closest bioactive conformation, and evaluated the early enrichment of bioactive-like conformations when ranking conformers by AtNN prediction. AtNN ranking was compared with bioactivity-unaware baselines such as ascending Sage force field energy ranking, and a slower bioactivity-based baseline ranking by ascending Torsion Fingerprint Deviation to the Maximum Common Substructure to the most similar molecule in the training set (TFD2SimRefMCS). On test sets from random ligand splits of PDBbind, ranking conformers using ComENet, the AtNN encoding the most 3D information, leads to early enrichment of bioactive-like conformations with a median BEDROC of 0.29 ± 0.02, outperforming the best bioactivity-unaware Sage energy ranking baseline (median BEDROC of 0.18 ± 0.02), and performing on a par with the bioactivity-based TFD2SimRefMCS baseline (median BEDROC of 0.31 ± 0.02). The improved performance of the AtNN and TFD2SimRefMCS baseline is mostly observed on test set ligands that bind proteins similar to proteins observed in the training set. On a more challenging subset of flexible molecules, the bioactivity-unaware baselines showed median BEDROCs up to 0.02, while AtNNs and TFD2SimRefMCS showed median BEDROCs between 0.09 and 0.13. When performing rigid ligand re-docking of PDBbind ligands with GOLD using the 1% top-ranked conformers, ComENet ranked conformers showed a higher successful docking rate than bioactivity-unaware baselines, with a rate of 0.48 ± 0.02 compared to CSD probability baseline with a rate of 0.39 ± 0.02. Similarly, on a pharmacophore searching experiment, selecting the 20% top-ranked conformers ranked by ComENet showed higher hit rate compared to baselines. Hence, the approach presented here uses AtNNs successfully to focus conformer ensembles towards bioactive-like conformations, representing an opportunity to reduce computational expense in virtual screening applications on known targets that require input conformations.

The microwave spectrum of the low energy conformers of 1-ethylsilacyclopentane

The microwave rotational spectrum of 1-ethylsilacyclopentane has been observed using chirped-pulse, Fourier transform microwave spectroscopy and has been reported for the first time. The lowest three energetic conformers were observed and fit to a Watson S semirigid Hamiltonian to within experimental accuracy. The quantum chemical calculations are all within ≈1% of the determined rotational constants, providing confidence that they are accurate representations of the experimental structure. Centrifugal distortion terms DJK and DK, although seemingly large, have been determined to be physically meaningful as no apparent evidence such as splittings in the spectrum or transition broadening was observed. A second moment analysis was undertaken and compared to similar silacyclopentanes, but it is not clear if this species follows previously determined trends.

Structural, Conformational and Spectroscopic Investigations of a Biologically Active Compound: L-Dopa

Structural, conformational and spectroscopic investigations of the L-dopa molecule were made at the b3lyp/6-311++g** level using the Gaussian 09 software. IR, Raman and UV-vis spectra were measured and analyzed in light of the computed spectral quantities. Total energy vs. dihedral angle scans yielded 108 pairs of stable conformers of L-dopa. All the conformers had energies above 500 K relative to the lowest-energy conformer C-I. The observed spectra could be explained in terms of the computed spectra of the lowest-energy dimer of the C-I monomer. MEP and HOMO-LUMO analysis were carried out, and barrier heights and bioactivity scores were determined. The positive bioactive scores represent its higher medicinal and pharmaceutical applications. The present investigation suggests that the molecule has three active sites with moderate bioactivity.

Comments on “Investigations on a novel biologically active organic molecule of 5-Chloro-1-(4-piperidyl)-2-benzimidazolinone by spectroscopic, molecular docking, and quantum chemical approach”

The conformational analysis for the 5-Chloro-1-(4-piperidyl)-2-benzimidazolinone molecule reported earlier [R. Arivazhagan, C. Sridevi, A. Prakasam, Investigations on a novel biologically active organic molecule of 5-Chloro-1-(4-piperidyl)-2-benzimidazolinone by spectroscopic, molecular docking, and quantum chemical approach, J. Mol. Struct. 1274 (2023) 134,544, 14 pages.] is incorrect. In the present communication we report briefly the correct conformational analysis. We have also discussed in brief the possible implications on different molecular properties on account of different molecular structures of the lowest energy conformer.

Spatial structure of soymorphin-6 molecule

By the method of the theoretic conformational analysis the conformational capabilities of the soymorphin-6 (Tyr1-Pro2-Phe3-Val4-Val5-Asn6-NH2) molecule were studied. The potential energy of this molecule is given as the sum of nonvalent, electrostatic and torsional interactions and the energy of hydrogen bonds. Low-energy conformations of the soymorphin-6 molecule, the values of the dihedral angles of the main and side chains of amino acid residues that make up the molecules are found, the energy of intra- and inter-residual interactions is estimated. It is shown that the spatial structure of the soymorphin-6 molecule can be represented by eight conformations. The results obtained can be used to study the structure and structural-functional organization of the soymorphin molecules.

Gas Phase Conformation of Trisaccharides and Core Pentasaccharide: A Three-Step Tree-Based Sampling and Quantum Mechanical Computational Approach.

As an important component of N-linked glycoproteins, the core pentasaccharide is highly crucial to the potential application prospect of glycoprotein. However, the gas phase conformation study is a challenging one due to the size and complexity of the molecule, together with the necessity to rely on quantum chemistry modeling for relevant energetics and structures. In this paper, the structures of the trisaccharides and core pentasaccharides in N-linked glycans in the gas phase were constructed by a three-step tree-based (TSTB) sampling. Since single point energies of all the conformers are calculated at the temperature of zero, it is necessary to evaluate the stability at a high temperature. We calculate the Gibbs free energies using the standard thermochemistry model (T = 298.15 K). For trimannose, the energetic ordering at 298.15 K can be strongly changed compared to 0 K. Moreover, two structures of trimannose with high energies at 0 K are considered to provide a much better match of IR vibration signatures with the low Gibbs free energies. On this basis, the core pentasaccharide was constructed in three ways. The building configurations of core pentasaccharide were optimized to obtain reasonable low-energy stable conformers. Fortunately, the lowest-energy structure of core pentasaccharide is eventually the minimum at 0 K and 298.15 K. Furthermore, spectrum analysis of core pentasaccharide was carried out. Although poorly resolved, its contour from the experiment was in qualitative correspondence with the computed IR spectrum associated with its minimum free energy structure. A large number of strongly and weakly hydrogen-bonded hydroxyl and acetylamino groups contribute to a highly congested set of overlapping bands. Compared with traditional conformation generators, the TSTB sampling is employed to efficiently and comprehensively obtain preferred conformers of larger saccharides with lower energy.

Molecular and qualitative characterization of compatibility between valacyclovir hydrochloride and excipients as raw materials for the development of solid oral dosage formulation

Objectives: The objective of this present study is to know the compatibility of valacyclovir hydrochloride (VCH) with common excipients that would be utilized to develop solid oral dosage forms. Several spectroscopy techniques were used to know the possible interactions of VCH with excipients. More, a molecular docking study was also carried out to see the interaction of VCH with excipients. In vitro study of a physical mixture of VCH with excipients was executed to know the release of a drug. Material and Methods: Several analytical techniques such as differential scanning calorimetry, nuclear magnetic resonance spectrometer, and Fourier-transform infrared (FTIR) spectroscopy have been utilized to know the drug-excipient compatibility. Further, possible interactions between valacyclovir and different excipients were assessed by thin-layer chromatography. In vitro dissolution studies in different sets of experiments were done to determine the influence of the hydrophobic and hydrophilic nature of excipients (on the dissolution profile of VCH using USP II-type dissolving apparatus). Moreover, in silico molecular docking studies were also done to know any possible molecular interactions among drugs and excipients using AutoDock VINA 1.2.0 software and GROMACS 5.0 software. Results: FTIR and 1H NMR spectra of VCH and physical mixtures of VCH and excipients were compared and it was observed that no significant deviation of characteristic peaks in infrared spectroscopy and 1H NMR signals was detected. The endothermic peak of VCH in the physical mixtures of drugs and excipients was found in approximately the same position. In vitro dissolution studies displayed the influence of the hydrophobic and hydrophilic nature of excipients on the dissolution profile of VCH. For the physical mixture of VCH with lactose (LAC) and dicalcium phosphate (DP), % drug release was found to be 31.96% and 33.16% at 10 min, whereas the amount of % drug released for the mixture of VCH and talc was 25.00%. For two other excipients such as LAC and DP, the % drug release was determined to be 42.96% and 41.64%, respectively, for 30 min. The docking study also provided insights into the lowest energy conformations. Docking study anticipated that the number of interactions were more between valacyclovir and LAC (four nos.) in comparison to valacyclovir and microcrystalline cellulose (MCC) (two nos.). This interaction showed that in vitro drug release for the physical mixture of VCH with MCC was higher than a mixture of valacyclovir with LAC. Conclusion: A compatibility study of VCH by analytical techniques established that VCH was compatible with utilized excipients. Drug dissolution of VCH and physical mixture of MCC exhibited the maximum amount of drug release whereas a mixture of VCH with magnesium stearate released the minimum amount of drug for both short (10 min.) and long (30 min.) period. Docking studies disclosed that the LAC complex showed less deviation with less root mean square deviation value in comparison to the microcrystalline complex. Thus, the LAC complex has more hydrogen bonds and it was more stable as compared with the MCC complex. Therefore, VCH and used excipients could be used for solid dose formulations.

Structure prediction of physiological bis(amino acidato)copper(II) species in aqueous solution: The copper(II) compounds with l-glutamine and l-histidine

Neutral (l-histidinato)(l-glutaminato)copper(II) [Cu(His)(Gln)] has been established as the most abundant ternary copper(II) amino acid compound of the exchangeable copper(II) pool in blood plasma. The experimental studies of Cu(His)(Gln) and bis(glutaminato)copper(II) [Cu(Gln)2] in solutions did not specify their complete geometries. To determine the geometries, this paper investigates the conformers, energy landscapes, and a structure–magnetic parameters relation of Cu(Gln)2 and Cu(His)(Gln) by the density functional theory (DFT) calculations. We assume a glycine-like coordination of Gln (other coordination patterns are dismissed because of steric reasons), and three His in-plane copper(II) binding modes. The conformational analyses are performed in the gas phase and implicitly modeled aqueous solution. The reliability of the DFT relative electronic and Gibbs free energies of the Cu(His)(Gln) conformers is confirmed by benchmarking against the corresponding energies obtained by the domain-based local pair natural orbital coupled-cluster method with singles, doubles, and perturbative triples [DLPNO-CCSD(T)]. Several cis- and trans-Cu(His)(Gln) conformers with His in the histaminate-like and glycine-like modes have low Gibbs free energies, and the greatest estimated metal-binding affinities. The DFT-calculated magnetic parameters of the low-energy conformers reproduce best the experimental electron paramagnetic resonance parameters measured in aqueous solutions for trans- and cis-Cu(Gln)2 conformers having two oxygen atoms (either from Gln or water molecules) at the apical positions, and Cu(His)(Gln) conformers having His in the histaminate-like mode with an apically placed carboxylato oxygen atom. The predicted conformational flexibility of His‑copper(II)-amino acid compounds may be connected with their physiological abundance, and the role in copper(II) exchange reactions in blood plasma.