Theoretical Conformational Analysis Research Articles

SPATIAL STRUCTURE OF THE HEPTAPEPTIDE ANALOGUE OF NOCICEPTIN MOLECULE

<p>It is known that nociceptins are a new type of regulatory peptide. Knowledge of these peptide molecules' structural and functional properties is of great practical importance for medicine and pharmacology. Their mechanisms of action are considered anti-opioid. This scientific work is devoted to studying the spatial structure of the heptapeptide H-Phe1-Gly2-Gly3-Phe4-Val5-Gly6-Pro7-OH. It examines the conformational capabilities of this heptapeptide molecule. This neuropeptide molecule is a stable analog of the nociceptin. The biologically active conformation of the peptide molecule, which is realized upon interaction with the receptor, is included in the set of low-energy structures. Therefore, studying the spatial structure of peptide molecules is of great interest. Theoretical conformational analysis about nonvalent, electrostatic, and torsional interactions, the energy of the hydrogen bonds, and a special computer program carried out the calculations. The 10 low-energy conformations of this molecule and the values of the dihedral angles of the main chain and side chains are found, and the energy of the intra- and inter-residue interactions is estimated. It is revealed that low energy conformations of this molecule have the half-folded and folded type of backbone. The side chains of the Phe1 and Phe4 amino acids in low-energy conformations carry out effective interactions and are conformationally labile amino acids; they bring together the regions of the main chain and the side chains of the amino acids included in the heptapeptide. These folded forms bring parts of the backbone and the amino acids' side chains together, resulting in important interactions.</p>

СТРУКТУРНАЯ ОРГАНИЗАЦИЯ ГЛИПРОЛИНОВОЙ ГЕКСАПЕПТИДНОЙ МОЛЕКУЛЫ

Computer modeling based on the use of the method of theoretical conformational analysis and programs that allow obtaining a graphic image of the spatial structures of biomolecules was performed for a hexapeptide molecule – glyproline H-Phe-Gly-Gly-Phe-Gly-Pro-OH. Glyprolines are short peptides whose amino acid sequences contain glycine and proline residues. Their mechanisms of action are currently poorly understood. Using the method of molecular mechanics, the spatial structure and conformational possibilities of this hexapeptide molecule were determined. Its potential energy was estimated as the sum of non-valente, electrostatic, torsion interactions and the energy of hydrogen bonds. 9 low-energy structures were found for the glyproline hexapeptide, the values of the dihedral angles of the main and side chains of the amino acids included in the molecule. The energy of intra- and interresidual interactions was estimated. The calculation showed that the folded forms of the main chain are low-energy for the hexapeptide. In them, the side chains of amino acids phenylalanine and proline, which are conformationally rigid, carry out effective interactions with all parts of the hexapeptide molecule.

СТРУКТУРНАЯ ОРГАНИЗАЦИЯ МОЛЕКУЛ СОЙМОРФИНОВ

The conformational capabilities of soymorphine-5 (Thr1-Pro2-Phe3-Val4-Val5-NH2), soymorphine-6 (Tyr1-Pro2-Phe3-Val4-Val5-Asn6-NH2) and soymorphine-7 (Tyr1- Pro2-Tyr3-Val4-Val5-Asn6-Ala7-NH2) molecules have been studied by the method of theoretical conformational analysis. The potential function of the system is chosen as the sum of non-valence, electrostatic and torsion interactions and the energy of hydrogen bonds. The low-energy conformations of soymorphine-5, soymorphine-6 and soymorphine-7 molecules were found, the dihedral angles of the main and side chains of amino acid residues that make up the molecule were found, and the energy of intra- and interresidual interactions was estimated. Thus, the spatial structure of soymorphine-5, soymorphine-6 and soymorphine-7 molecules can be represented by eight structural types. It can be assumed that the molecules perform their physiological functions in these structures. Comparison of the low-energy structures of soymorphins shows that in all molecules the first four low-energy conformations are representatives of the structural types efef, efee, efff, effe for soymorphine-5, effff, efeff, efffe, effee for soymorphine-6, efffff, efeffe, efffef, effeee for soymorphine-6. soymorphine-7. On the basis of these structures, it is possible to propose their artificial analogues for synthesis. It was shown that the spatial structure of soymorphine-5, soymorphine-6 and soymorphine-7 molecules is represented by the conformations of eight shapes of the peptide skeleton. The results obtained can be used to elucidate the structural and structural-functional organization of soymorphine molecules.

Spatial Structure of the Casoxin D Molecule

ABSTRACT The conformational possibilities of the casoxin D (Tyr1-Val2-Pro3-Phe4-Pro5-Pro6-Phe7) molecule were studied by theoretical conformational analysis. The potential function of the system is chosen as the sum of non-valence, electrostatic and torsion interactions and the energy of hydrogen bonds. The low-energy conformations of the casoxin D molecule, the dihedral angles of the main and side chains of the amino acid residues that make up the molecule were found, and the energy of intra- and interresidual interactions was estimated. It has been shown that the spatial structure of the casoxin D molecule is represented by conformations of eight shapes of the peptide skeleton. The results obtained can be used to elucidate the structural and structural-functional organisation of casoxin molecules.

Structure of Tris[2-(4-pyridyl)ethyl]phosphine, Tris[2-(2-pyridyl)ethyl]phosphine, and Their Chalcogenides in Solution: Dipole Moments, IR Spectroscopy, and DFT Study.

Tris(hetaryl)substituted phosphines and their chalcogenides are promising polydentate ligands for the design of metal complexes. An experimental and theoretical conformational analysis of tris[2-(4-pyridyl)ethyl]phosphine, tris[2-(2-pyridyl)ethyl]phosphine, and their chalcogenides was carried out by the methods of dipole moments, IR spectroscopy and DFT B3PW91/6-311++G(df,p) calculations. In solution, these compounds exist as an equilibrium of mainly non-eclipsed (synclinal or antiperiplanar) forms with a predominance of a symmetrical conformer having a gauche-orientation of the Csp3-Csp3 bonds of pyridylethyl substituents relative to the P=X bond (X = lone pair, O, S, Se) and a gauche-orientation of the pyridyl rings relative to the zigzag ethylene bridges. Regardless of the presence and nature of the chalcogen atom (oxygen, sulfur, or selenium) in the studied molecules with many axes of internal rotation, steric factors-the different position of the nitrogen atoms in the pyridyl rings and the configuration of ethylene bridges-determine the realization and spatial structure of preferred conformers.

Analgesic Effect of the Lysine-Containing Short Peptide Is Due to Modulation of the NaV1.8 Channel Activation Gating System.

The present work continues our recent series of articles that aim to elucidate the ligand-receptor binding mechanism of short cationic peptides to the NaV1.8 channel in the nociceptive neuron. The applied methodological approach has involved several methods: the patch-clamp experimental evaluation of the effective charge of the NaV1.8 channel activation gating system, the organotypic tissue culture method, the formalin test, and theoretical conformational analysis. The lysine-containing short peptide Ac-KEKK-NH2 has been shown to effectively modulate the NaV1.8 channel activation gating system. As demonstrated by the organotypic tissue culture method, the studied short peptide does not trigger the downstream signaling cascades controlling neurite outgrowth and should not be expected to evoke adverse side effects. Conformational analysis of the Ac-KEKK-NH2 molecule has revealed that the distances between the positively charged amino groups of the lysine side chains are equal to 11-12 Å. According to the previously suggested mechanism of ligand-receptor binding of short peptides to the NaV1.8 channel molecule, Ac-KEKK-NH2 should exhibit an analgesic effect, which has been confirmed by the formalin test. The data obtained unequivocally indicate that the studied lysine-containing short peptide is a promising candidate for the role of a novel analgesic medicinal substance.

Synthesis, Biological Activity, and the Effect of Ionization Radiation on the Spectral, XRD, and TGA Analysis of Cu(I), Cu(II), Zn(II), and Cd(II) Complexes

New complexes of molecular formulae of [Cu(H2L1)I] (B1), [Cu(H2L)2(ClO4)2](B2), [Zn (H2L)2(H2O)]SO4(B3) and [Cd(H2L)Cl]Cl(B4) of ligand N-phenyl-2-(p-tolylglycyl)hydrazine -1-carbothioamide (B) have been prepared and characterized by 1H-NMR, Mass spectra, FT-IR, elemental analyses, molar conductance, UV–visible spectra, magnetic susceptibility measurements, thermogravimetric analysis (TGA/DTG) and X-ray powder diffraction before and after irradiation. Elemental analyses indicate that the metal complexes have 1:1 (metal/ ligand) (B1 and B4) or 1:2 stoichiometry for complexes (B2 and B3). The results confirmed that gamma ray enhanced the stability of irradiated compounds as compared to non-irradiated compounds. XRD patterns proved that increasing the crystallinity of the samples and the particles is in nanosize range before and after gamma irradiation. These studies revealed that Cu(II) and Zn(II) complexes adopted octahedral geometry, and Cu(I) and Cd(II) complexes were found to be tetrahedral. The theoretical conformational structure analyses were performed using density functional theory for ligand and complexes at B3LYP functional with 6–31G basis set for ligand and LANL2DZ basis set for complexes. The ligand (B, A) and complexes (B1–B4) and (A1–A4) before and after irradiated have been tested for their inhibitory effect on the growth of bacteria against gram-positive (Streptococcus pyogenes) and gram-negative (Escherichia coli). Molecular docking investigation proved that the Zn(II) complex had interesting interactions with active site amino acids of topoisomerase II DNA gyrase enzymes (code: 2XCT).

Rapid determination of the relative configuration of diverse 8,4′-oxyneolignans by NMR analysis: Retrospective studies, improvement and structural revision

The characteristic 1H NMR signals (H-7 and H2-9) are significant parameters that have been widely used to assess the relative configuration of H-7 and H-8 of 8,4′-oxyneolignans. However, many usual 8,4′-oxyneolignans cannot be accurately determined by existing NMR methods and no research considering their limitations was performed until now. In this study, the application scope of NMR methods was comprehensively studied and the ΔδH9a–H9b methods have been extended to solve the majority of configuration determination difficulties. The accuracy of extended NMR methods was verified by anisotropic NMR (RCSA measurements), NMR calculation and diverse statistical analysis (MAEΔΔδ, CP3 and DP4+). Furthermore, the theoretical conformational analysis was performed to investigate the inherent limitations of existing NMR methods. This study could provide a valuable reference for determining the relative configuration of H-7 and H-8 in 8,4′-oxyneolignans and the relative configuration of 23 recently reported 8,4′-oxyneolignan derivatives should be reassigned as well.

Трехмерная структура молекулы бета-лакторфина

Opioid peptides cause pain relief, sedation and sleep, as well as a euphoric state and a number of autonomic reactions. These peptides are of animal and plant origin. A number of exogenous peptides obtained from food have opiate-like properties. This peptides were named exorphins. The discovery of the opioid activity of the peptide components of food has led to the assumption that certain types of food can act on the central nervous system like opiate drugs. A number of milk exorphins have been found that have opioid receptor antagonist properties. These include casoxins A, B, C, human casoxin D, as well as lactoferroxins A, B and C, as well as alpha and beta lactorphins. The possibility of the formation of these peptides during the hydrolysis of the corresponding proteins by peptidases of the gastrointestinal tract has been proven in vitro. Representatives of exorphins are also cytochrophins and hemorphins. It is assumed that these peptides can be formed in vivo during the proteolytic cleavage of cytochrome b and hemoglobin. The beta-lactorphine molecule is a representative of this class. The conformational possibilities of the beta-lactorphine Tyr-Leu-Leu-Phe molecule were studied by the method of theoretical conformational analysis. The potential function of the system is chosen as the sum of non-valence, electrostatic and torsion interactions and the energy of hydrogen bonds. The low-energy conformations of the alpha-lactorphine molecule, the values of the dihedral angles of the main and side chains of the amino acid residues that make up the molecules were found, and the energy of intra- and interresidual interactions was estimated. It has been shown that the spatial structure of the beta-lactorphine molecule can be represented by eight forms of the main chain. The results obtained can be used to elucidate the structural and structural-functional organization of exorphin molecules.

Proton tautomerism and stereoisomerism of 4-amino-1,3-thiazol-2(5H)-one derivatives bearing substituents with opposite electronic effects: Synthesis, structure and spectroscopic studies

New compounds of high pharmacological interest: 5-dimethylaminomethylidene-4-phenylamino-1,3-thiazol-2(5H)-one and 5-methoxycarbonylmethylidene-4-phenylamino-1,3-thiazol-2(5H)-one, were synthesized and investigated. Their crystal structure, chemical environment, and intermolecular interactions were studied by X-ray diffraction method and by NMR and FT-IR spectroscopy. The molecular interactions in the crystals were analyzed using Density Functional Theory (DFT), Quantum Theory of Atoms in Molecules (QTAIM), Hirshfeld surfaces, and fingerprint plots, with special emphasis on stereoisomerism and proton tautomerism. Both investigated compounds occur in the solution (DMSO) and in the solid state in the amine tautomeric form. The ylidene substituent with electron-donating effect only could significantly decrease the resonance effect of the carbonylimino group with the phenylamino moiety. In the molecules of both compounds, the phenylamino group has a synperiplanar conformation, and the ylidene substituent has the Z configuration. The theoretical conformational analysis shows that the coplanar arrangement of the thiazolin-2-one and phenyl systems is preferred.

Discovery of Cyclic Diarylheptanoids as Inhibitors against Influenza A Virus from the Roots of Casuarina equisetifolia.

Four new cyclic diarylheptanoids, casuarinols A-C (1-3) and casuarinolide A (4), together with six known ones (5-10), were isolated from the roots of Casuarina equisetifolia. Structures were elucidated by extensive spectroscopic analysis, theoretical conformational, and electronic circular dichroism analyses. Casuarinol C (3) is a novel cyclic diarylheptanoid-aldehyde adduct. Casuarinolide A (4) represents the first structure of a seco-cyclic diarylheptanoid. Compounds 1-9 were evaluated for their anti-influenza A virus (IAV) activity against A/WSN/33 (H1N1). (-)-(M)-11-Oxo-3,12R,17-trihydroxy-9-ene-[7,0]-metacyclophane (5) displayed significant anti-IAV activity with an IC50 value of 8.64 ± 2.49 μM and a CC50 higher than 100 μM.

Pharmacophore Based Design, Synthesis and Theoretical Conformational Analysis of Some Extended Aryl Hydrazones as Potential Anticonvulsant

A series of hydrazones were synthesized by condensing substituted hydrazides with appropriate carbonyl compounds. The chemical structures of the synthesized compounds were confirmed by infrared, proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance, mass ((4-chloro-phenylamino)-acetic acid [1-(4-chlorophenyl)-phenyl-methylene]-hydrazide and (2,4-dichloro-phenylamino)-acetic acid (3-oxo- 1,3-dihydro-indole-2-ylidene)-hydrazide only) spectral data and carbon hydrogen nitrogen analysis. The title compounds were screened for their anticonvulsant activity against mice at doses of 30 mg/kg, 100 mg/kg and 300 mg/kg. The preliminary anticonvulsant screening data of this series resulted in the identification of two lead compounds (2,4-dichloro-phenylamino)-acetic acid (3-oxo-1,3-dihydro-indole- 2-ylidene)-hydrazide and (2,4-dichloro-phenylamino)-acetic acid [1-(4-chlorophenyl)-phenyl-methylene]- hydrazide with excellent preliminary anticonvulsant profile with no neurotoxicity in maximal electroshock seizure and subcutaneous metrazol mice model.

Conformational Analysis of N-Alkyl-N-[2-(diphenylphosphoryl)ethyl]amides of Diphenylphosphorylacetic Acid: Dipole Moments, IR Spectroscopy, DFT Study.

Experimental and theoretical conformational analysis of N-methyl-N-[2-(diphenylphosphoryl)ethyl]diphenylphosphorylacetamide, N-butyl-N-[2-(diphenylphosphoryl)ethyl]diphenylphosphorylacetamide, and N-octyl-N-[2-(diphenylphosphoryl)ethyl]diphenylphosphorylacetamide was carried out by the methods of dipole moments, IR spectroscopy, and Density Functional Theory (DFT) B3PW91/6-311++G(df,p) calculations. In solution, these N,N-dialkyl substituted bisphosphorylated acetamides exist as a conformational equilibrium of several forms divided into two groups—with Z- or E-configuration of the carbonyl group and alkyl substituent, and syn or anti arrangement of the phosphoryl-containing fragments relative to the amide plane. The substituents at the phosphorus atoms have eclipsed cis- or staggered gauche-orientation relative to the P=O groups, and cis orientation of the substituents is due to the presence of intramolecular H-contacts P=O...H−Cphenyl or p,π conjugation between the phosphoryl group and the phenyl ring. Preferred conformers of acetamides molecules are additionally stabilized by various intramolecular hydrogen contacts with the participation of oxygen atoms of the P=O or C=O groups and hydrogen atoms of the methylene and ethylene bridges, alkyl substituents, and phenyl rings. However, steric factors, such as a flat amide fragment, the bulky phenyl groups, and the configuration of alkyl bridges, make a significant contribution to the realization of preferred conformers.

STUDY OF STABLE STRUCTURES OF THE PENTAPEPTIDE MOLECULE

Low-energy conformational states of the CREKA molecule, a new drug with an antitumor effect, have been studied by the method of theoretical conformational analysis. Geometric parameters and energy contributions of various types of interatomic interactions to the stabilization of the calculated structures have been established.

Stabilization of glyphosate zwitterions and conformational/tautomerism mechanism in aqueous solution: insights from ab initio and density functional theory-continuum model calculations.

In this work, a comparative theoretical conformational analysis of the commercially most successful herbicide compound, glyphosate (N-phosphonomethylglycine), has been made at various quantum chemical levels of theory, in the gas phase and aqueous solution, using the integral equation-formalism polarizable continuum model (IEFPCM) and the solvation model density (SMD) approaches. The stable conformers of non-ionized (NE) and ionized or zwitterionic (ZW) neutral forms of glyphosate and the inter-conversions between them are described. Calculations revealed that several NE conformers of glyphosate exist in the gas phase but the zwitterionic form (ZW) is unstable in vacuo at all levels of theory. In aqueous solution, the stabilization of the zwitterion form of glyphosate was unable to be predicted satisfactorily within the equilibrated framework of the IEFPCM polarizable continuum model and using the standard UFF-radii cavity. However, the calculation with the density-based solvation model (SMD) was consistent with the experimental findings and led to the identification of the phosphonate zwitterionic (ZWP) structure as the global minimum energy in aqueous solution. The ZWP ⇋ NE tautomeric equilibrium between the non-ionized and zwitterionic forms of glyphosate was studied in aqueous solution at the SMD-B3LYP-D3/6-311++(2d,2p) level. Zwitterion formation in solution could occur by means of a concerted intramolecular proton transfer from the nitrogen to the oxygen of the phosphonate group. An analysis of the intermolecular mechanism shows that the addition of one water molecule favours the process either thermodynamically or kinetically. The possibility that the tautomerization process of glyphosate via a nonconcerted mechanism with zwitterion carboxylate (ZWC) as the intermediate can be excluded and the ZWP → ZWC proton transfer conversion can be a nearly barrierless process in PES and FES surfaces. comparison with similarly related biologically active systems was made.

Spatial Structure of the Acth-(6-9)-PGP Molecule

The spatial structure of ACTH-(6-9)-PGP molecule has been investigated using theoretical conformational analysis method. Amino acid sequence of the N-terminal pentapeptide fragment of His-Phe-Arg-Trp-Pro of this molecule conforms to the fragment 6-9 of ACTH hormone. Calculations of conformational states of this molecule are carried out regarding nonvalent, electrostatic and torsional interactions and the energy of hydrogen bonds. The spatial structure of the His-Phe-Arg-Trp-Pro-Gly-Pro molecule was estimated on the low–energy conformations of the N-terminal tetrapeptide fragment His-Phe-Arg-Trp and C-terminal tripeptide fragment Pro-Gly-Pro of this molecule. It is shown that the spatial structure of heptapeptide molecule can be presented by 11 low-energy forms of the main chain. The low–energy conformations of this molecule, the values of dihedral angles of the backbone and side chains of the amino acid residues were founded and the energies of intra- and inter-residual interactions were determined.

Spatial Structure of the Acth-(6-9)-PGP Molecule

The spatial structure of ACTH-(6-9)-PGP molecule has been investigated using theoretical conformational analysis method. Amino acid sequence of the N-terminal pentapeptide fragment of His-Phe-Arg-Trp-Pro of this molecule conforms to the fragment 6-9 of ACTH hormone. Calculations of conformational states of this molecule are carried out regarding nonvalent, electrostatic and torsional interactions and the energy of hydrogen bonds. The spatial structure of the His-Phe-Arg-Trp-Pro-Gly-Pro molecule was estimated on the low–energy conformations of the N-terminal tetrapeptide fragment His-Phe-Arg-Trp and C-terminal tripeptide fragment Pro-Gly-Pro of this molecule. It is shown that the spatial structure of heptapeptide molecule can be presented by 11 low-energy forms of the main chain. The low–energy conformations of this molecule, the values of dihedral angles of the backbone and side chains of the amino acid residues were founded and the energies of intra- and inter-residual interactions were determined.

Synthesis of aminal-type Lilium candidum alkaloids and lilaline; determination of their relative configuration by the concerted use of NMR spectroscopy and DFT conformational analysis

Abstract We hereby report the synthesis of six racemic alkaloids isolated from Lilium candidum L. Their common structural feature is a five-membered lactam ring which is, in the case of the flavonoid alkaloid lilaline, attached to the molecule’s aromatic core, while in the case of the other five compounds, it is connected to the nitrogen atom of a pyrrolinone ring by an aminal function. The syntheses of these natural products were achieved via Mannich-type alkylations through cyclic N-acyliminium ions as intermediates. Besides the synthesis, the so far unexplored stereochemistry of these natural products was determined by a combination of NMR-based proton–proton distance measurements and theoretical conformational analyses carried out at the DFT level.

Experimental and Theoretical Conformational Analysis of Tris(4-methylphenyl)phosphine and Its Chalcogenides

Conformational analysis of tris(4-methylphenyl)phosphine and its oxide, sulfide, and selenide has been performed by the dipole moment method and DFT quantum chemical calculations at the B3PW91/ 6-311++G(df,p) level of theory. The title compounds have been found to exist in solution as a single symmetrical conformer with gauche,gauche,gauche orientation of the substituents on the phosphorus atom with respect to the P=X bond (X = LEP, O, S, Se).

Exploiting isohexide scaffolds for the preparation of chiral ionic liquids tweezers

New bis-quinolinium chiral ionic liquids (CILs) were synthesized in good yields starting from isomannide and isosorbide by a straightforward procedure that maintains the absolute stereostructure of the isohexide scaffolds. Thermal gravimetric analysis and differential scanning calorimetry, aimed at investigating the short thermal stability and the thermal behaviour of the synthesized ionic compounds are presented. The stereochemical features of both ionic derivatives and their neutral precursors were investigated by electronic circular dichroism (ECD) spectroscopy. ECD spectra of neutral compounds 5 and 6 and their N-methylated cations (5-Me+ and 6-Me+) were theoretically investigated by means of molecular modelling and excited-state calculations. A theoretical conformational analysis suggests the possible use of the isohexide derivatives as tweezers-type hosts in recognition processes toward different kinds of guests. Some of the ionic derivatives were successfully used in the NMR enantiorecognition of TFAE, discriminating the enantiomers through a tweezers-like mechanism.