Theoretical study of the conformational states of triosmium clusters with a chiral pinane ligand

A theoretical study of the conformational state of triosmium clusters with a chiral pinane ligand (μ-H)Os₃(CO)₁₀(μ-ONC₁₀H₁₄) has been performed. The potential curves of internal rotation of organic ligands around the N-C bond in cluster complexes in the crystalline state and in various solvents with continual consideration for the parameters of the latter have been determined. The structures of conceivable conformers and isomers are considered; the factors responsible for their formation and stability are examined. The relations between the conformational and crystalline structures of the cluster and the effect of intra-and intermolecular interactions on its structure are revealed.     

Superimposition evaluation of ecdysteroid agonist chemotypes through multidimensional QSAR

The EC₅₀ values for a training set of 66 ecdysteroids and 97 diacylhydrazines were measured in the ecdysteroid-responsive Drosophila melanogaster B_II cell line, a prototypical homologous inducible gene expression system. Each of eight superimposition hypotheses for the folded diacylhydrazine conformation was evaluated and ranked on the basis of CoMFA and 4D-QSAR Q² values for the training set and R² values for a 52-member test set comprising randomly-chosen diacylhydrazines and chronologically-chosen ecdysteroids for which data became available after model construction. Both 4D-QSAR and CoMFA rate a common superimposition as the preferred one. Two additional superimpositions, with somewhat weaker 4D-QSAR and CoMFA consensus, nonetheless share several important topological features. The resultant QSAR models address the question of relative binding orientation of the two ligand families and can be useful as a virtual screen for new chemotypes.     

Solvent and temperature effects on the conformational equilibria of a dihydrobenzo[h]quinolinium fluoroborate

Spectra of the N‐phenyl‐5,6‐dihydro‐2,4‐diphenylbenzo[h]quinolinium tetrafluoroborate (1) and of the N‐phenyl‐5,6,8,9‐tetrahydro‐7‐phenyldibenzo[c,h]acridinium tetrafluoroborate (2) were recorded in various solvents and temperatures. The analysis of the ¹H‐NMR spectra of the tetrafluoroborate salt 1, recorded in acetone, acetonitrile, 1,1,2,2‐tetrachloroethane and chloroform, revealed the existence of an equilibrium between two conformers in solution. Tight ion‐pairing in chloroform led to a smaller barrier for interconversion between the two conformers. In more polar solvents, where the dihydrobenzoquinolinium exists as a free cation, theoretical calculations predicted larger barriers. The spectra of 1 in 1,1,2,2‐tetrachloroethane also varied with temperature, resembling at higher temperatures the spectrum in CDCl₃ and at 300K spectra in more polar media. Spectra of 2 did not vary with the solvent or the temperature, in an indication of a much higher barrier to conformational interconversion, because of a greater steric hindrance between the N‐phenyl substituent and the dihydrobenzo rings. Copyright © 2009 John Wiley & Sons, Ltd.     

Inhibitors of prolyl endopeptidase: Characterization of the pharmacophoric pattern using conformational analysis and 3D-QSAR

Summary A structure-activity study has been carried out on several compounds known as inhibitors of the serine protease prolyl endopeptidase. Conformational analysis has been done using different molecular mechanics methods such as molecular dynamics, or a randomized conformational search method. The conformers obtained were classified using geometric and energetic criteria. A pattern recognition analysis was done in order to divide conformers according to families. The resulting dominant families, for all compounds investigated, showed very similar geometric features. Based on the lowest energy conformers obtained after randomized conformational analysis, a 3D-QSAR model was established using the CoMFA approach. The validity of this model was verified by prediciting correctly the activity of other molecules not used in the construction of this model.     

Molecular modeling for Cu(II)‐aminopolycarboxylate complexes: Structures,conformational energies,and ligand binding affinities

A ligand field molecular mechanics (LFMM) force field (FF) has been developed for d⁹ copper(II) complexes of aminopolycarboxylate ligands. Training data were derived from density functional theory (DFT) geometry optimizations of 14 complexes comprising potentially hexadentate N₂O₄, tetrasubstituted ethylenediamine (ed), and propylenediamine cores with various combinations of acetate and propionate side arms. The FF was validated against 13 experimental structures from X‐ray crystallography including hexadentate N₂O₄ donors where the nitrogens donors are forced to be cis and bis‐tridentate ONO ligands which generate complexes with trans nitrogen donors. Stochastic conformational searches for [Cu{ed(acetate)_n (propionate)_4‐n}]^2?, n = 0–4, were carried out and the lowest conformers for each system reoptimized with DFT. In each case, both DFT and LFMM predict the same lowest‐energy conformer and the structures and energies of the higher‐energy conformers are also in satisfactory agreement. The relative interaction energies for n = 0, 2, and 4 computed by molecular mechanics correlate with the experimental log β binding affinities. Adding in the predicted log β values for n = 1 and 3 suggest for this set of complexes a monotonic decrease in log β as the number of propionate arms increases. © 2013 Wiley Periodicals, Inc.     

Targeting the Rich Conformational Landscape of N-Allylmethylamine Using Rotational Spectroscopy and Quantum Mechanical Calculations

The highly variable conformational landscape of N-allylmethylamine (AMA) was investigated using Fourier transform microwave spectroscopy aided by high-level theoretical calculations to understand the energy relationship governing the interconversion between nine stable conformers. Spectroscopically, transitions belonging to four low energy conformers were identified and their hyperfine patterns owing to the ¹⁴N quadrupolar nucleus were unambiguously resolved. The rotational spectrum of the global minimum geometry, conformer I, shows an additional splitting associated with a tunneling motion through an energy barrier interconnecting its enantiomeric forms. A two-step tunneling trajectory is proposed by finding transition state structures corresponding to the allyl torsion and NH inversion. Natural bond orbital and non-covalent interaction analyses reveal that an interplay between steric and hyperconjugative effects rules the conformational preferences of AMA.     

The 3D Structure of the Binding Pocket of the Human Oxytocin Receptor for Benzoxazine Antagonists,Determined by Molecular Docking,Scoring Functions and 3D-QSAR Methods

Summary Molecular docking and 3D-QSAR studies were performed to determine the binding mode for a series of benzoxazine oxytocin antagonists taken from the literature. Structural hypotheses were generated by docking the most active molecule to the rigid receptor by means of AutoDock 3.05. The cluster analysis yielded seven possible binding conformations. These structures were refined by using constrained simulated annealing, and the further ligands were aligned in the refined receptor by molecular docking. A good correlation was found between the estimated ΔG_bind and the pK_i values for complex F. The Connolly-surface analysis, CoMFA and CoMSIA models q_CoMFA² = 0.653, q_CoMSA² = 0.630 and r_pred,CoMFA² = 0.852 , r_pred,CoMSIA² = 0.815) confirmed the scoring function results. The structural features of the receptor–ligand complex and the CoMFA and CoMSIA fields are in closely connected. These results suggest that receptor–ligand complex F is the most likely binding hypothesis for the studied benzoxazine analogs.     

Chemical shift assignment and conformational analysis of monoalkylated acylguanidines

Monoalkylated acylguanidines are important functional groups in many biologically active compounds and additionally applied in coordination chemistry. Yet a straightforward assignment of the individual NH chemical shifts and the acylguanidine conformations is still missing. Therefore, in this study, NMR spectroscopic approaches for the chemical and especially the conformational assignment of protonated monoalkylated acylguanidines are presented. While NOESY and ³J_{H, H} scalar couplings cannot be applied successfully for the assignment of acylguanidines, ⁴J_{H, H} scalar couplings in ¹H,¹H COSY spectra allow for an unambiguous chemical shift and conformational assignment. It is shown that these ⁴J_{H, H} long‐range couplings between individual acylguanidinium NH resonances are observed solely across all‐trans (w) pathways. Already one cis orientation in the magnetisation transfer pathway leads to signal intensities below the actual detection limit and significantly lower than cross‐peaks from ²J_{NH, NH} couplings or chemical exchange. However, it should be noted that also in the case of conformational exchange being fast on the NMR time scale, averaged cross‐peaks from all‐trans ⁴J_{H, H} scalar couplings are detected, which may lead at first glance to an incomplete or even wrong conformational analysis. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis,crystal structure and conformational analysis of an unexpected [1,5]dithiocine product of aminopyridine and thiovanillin

The condensation reaction of 2‐mercapto‐3‐methoxybenzaldehyde with 3‐aminopyridine afforded an unexpected N‐alkylated [1,5]dithiocine instead of the N‐salicylideneaniline. The proposed mechanism for this condensation involves a strong intramolecular hydrogen bond between the thiol and the amine groups, leading to a second condensation. The corresponding product, i.e. 4,10‐dimethoxy‐13‐(pyridin‐3‐yl)‐6H,12H‐6,12‐epiminodibenzo[b,f][1,5]dithiocine methanol 0.463‐solvate, C₂₁H₁₈N₂O₂S₂·0.463CH₃OH, was characterized by single‐crystal X‐ray diffraction analysis. The supramolecular structure shows π–π stacking and S…S interactions in the crystal packing. Within the asymmetric unit, two geometries of the N atom are observed. Although a planar geometry should be expected, a pyramidal one is observed due to the crystal packing. The presence of the two geometries was further supported by density functional theory (DFT) calculations that show an electronic energy difference of less than 2 kJ mol^?1 between the two conformers.     

NMR spectroscopic conformational analysis of 4‐methylene‐cyclohexyl pivalate—The effect of sp2 hybridization

The conformational equilibrium of the axial/equatorial conformers of 4‐methylene‐cyclohexyl pivalate is studied by dynamic NMR spectroscopy in a methylene chloride/freon mixture. At 153 K, the ring interconversion gets slow on the nuclear magnetic resonance timescale, the conformational equilibrium (?ΔG°) can be examined, and the barrier to ring interconversion (ΔG^#) can be determined. The structural influence of sp² hybridization on both ΔG° and ΔG^# of the cyclohexyl moiety can be quantified.     

Conformational polymorphism in a cobalt(II) dithiocarbamate complex

Two conformational polymorphs of (N,N‐dibutyldithiocarbamato‐κ²S,S′)[tris(3,5‐diphenylpyrazol‐1‐yl‐κN²)hydroborato]cobalt(II), [Co(C₄₅H₃₄BN₆)(C₉H₁₈NS₂)] or [Tp^Ph2Co(S₂CNBu₂)], 1 , are accessible by recrystallization from dichloromethane–methanol to give orthorhombic polymorph 1a , while slow evaporation from acetonitrile produces triclinic polymorph 1b . The two polymorphs have been characterized by IR spectroscopy and single‐crystal X‐ray crystallography at 150 K. Polymorphs 1a and 1b crystallize in the orthorhombic space group Pbca and the triclinic space group P, respectively. The polymorphs have a trans ( 1a ) and cis ( 1b ) orientation of the butyl groups with respect to the S₂CN plane of the dithiocarbamate ligand, which results in an intermediate five‐coordinate geometry for 1a and a square‐pyramidal geometry for 1b . Hirshfeld surface analysis reveals minor differences between the two polymorphs, with 1a exhibiting stronger C—H…S interactions and 1b favouring C—H…π interactions.     

Strategies to design pyrazolyl urea derivatives for p38 kinase inhibition: a molecular modeling study

The p38 protein kinase is a serine–threonine mitogen activated protein kinase, which plays an important role in inflammation and arthritis. A combined study of 3D-QSAR and molecular docking has been undertaken to explore the structural insights of pyrazolyl urea p38 kinase inhibitors. The 3D-QSAR studies involved comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA). The best CoMFA model was derived from the atom fit alignment with a cross-validated r ² (q ²) value of 0.516 and conventional r ² of 0.950, while the best CoMSIA model yielded a q ² of 0.455 and r ² of 0.979 (39 molecules in training set, 9 molecules in test set). The CoMFA and CoMSIA contour maps generated from these models provided inklings about the influence of interactive molecular fields in the space on the activity. GOLD, Sybyl (FlexX) and AutoDock docking protocols were exercised to explore the protein–inhibitor interactions. The integration of 3D-QSAR and molecular docking has proffered essential structural features of pyrazolyl urea inhibitors and also strategies to design new potent analogues with enhanced activity.     

Temperature‐dependent conformational analysis of cyclononane: An ab initio study

Quantum chemical methods were used for the theoretical determination of the conformational population for the relevant conformers of cyclononane, i.e., TBC, TCB, TCC, and M4 (or C1), which have been previously investigated experimentally through detailed examination of the nuclear magnetic resonance (NMR) spectrum. Our best Gibbs free energy result, evaluated with MP4(SDTQ)/6‐31G(d,p)//MP2/6‐31G(d,p) energy differences and MP2/6‐31G(d,p) thermal corrections, lead to a temperature‐dependent population in excellent agreement with the experimental results based on the analysis of the low temperature ¹³C NMR spectrum. The nice agreement with experiment is achieved using MP2 harmonic frequencies for the evaluation of vibration partition functions within the standard statistic thermodynamics formalism. Theoretical temperature‐dependent infrared (IR) and ¹³C NMR spectra were simulated and compared with experimental data, which confirmed the ab initio conformational population reported here. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

CoMFA and CoMSIA studies on a new series of xanthone derivatives against the oral human epidermoid carcinoma (KB) cancer cell line

Abstract  A new series of xanthone derivatives against the oral human epidermoid carcinoma (KB) cancer cell line is examined to determine the relationship between the structural properties and the biological activity of these compounds—the 3-D quantitative structure–activity relationship (3D-QSAR)—using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best CoMFA and CoMSIA models were obtained using the atom-based alignment of 33 compounds, 22 training compounds and 11 tested compounds, and these give desirable statistics; those for the CoMFA standard model were: r _cv² = 0.691, r ² = 0.998, S _press = 0.178, s = 0.014 and F = 1080.765, while CoMSIA combined steric, electrostatic, hydrophobic and hydrogen-bond acceptor fields: r _cv² = 0.600, r ² = 0.988, S _press = 0.206, s = 0.034 and F = 284.433. The 3D-QSAR models calculated satisfactory test set activities. The 3D-QSAR contour plots correlated strongly with the experimental data for the binding topology. For this reason, these results would be beneficial for predicting affinities with the compounds of interest, and they are advantageous for guiding the design and synthesis of new and more effective anticancer agents. Graphical abstract   A new and more effective anticancer agent of xanthone derivatives against the oral human epidermoid carcinoma (KB) cell line, as investigated by CoMFA and CoMSIA analysis     

3D-QSAR (CoMFA,CoMSIA, HQSAR and topomer CoMFA), MD simulations and molecular docking studies on purinylpyridine derivatives as B-Raf inhibitors for the treatment of melanoma cancer

As per the World Health Organization (WHO), cancer is the second most leading cause of death after cardiovascular diseases in worldwide with around 9.88 million total new cases and 1.08 million were observed due to skin cancer in 2018. Amongst two types of skin cancer, progression of melanoma cancer is increasing day by day due to the environmental changes than non-melanoma cancer. Most of B-Raf mutation, specifically B-RafV600E, is responsible for the progression of the melanoma cancer. Here, various 3D-QSAR techniques like comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), molecular hologram QSAR (HQSAR) and topomer CoMFA were used to design novel B-Raf inhibitors by using 28 synthetic B-Raf inhibitors. Except for topomer CoMFA model, remaining models were generated by three different alignment methods in which distil-based alignment method was found best and gave prominent statistical values. After performing N-fold statistical validation, in CoMFA, q², r² and r²_pred values were found to be 0.638, 0.969 and 0.848, respectively. Similarly, q², r² and r²_pred values were found to be 0.796, 0.978 and 0.891 in CoMSIA (SHD) and 0.761, 0.973 and 0.852 in CoMSIA (SH) by N-fold statistical validation. In HQSAR analysis, statistical values were found for q² as 0.984, r² as 0.999 and r²_pred as 0.634 with 97 as best hologram length (BHL). The results of topomer CoMFA showed the q² value of 0.663 and the r² value of 0.967. Important features of purinylpyridine were identified by contour map analysis of all 3D-QSAR techniques, which could be useful to design the novel molecules as B-Raf inhibitors for the treatment of melanoma cancer.

     

CoMFA and CoMSIA studies on a new series of xanthone derivatives against the oral human epidermoid carcinoma (KB) cancer cell line

Abstract  

A new series of xanthone derivatives against the oral human epidermoid carcinoma (KB) cancer cell line is examined to determine the relationship between the structural properties and the biological activity of these compounds—the 3-D quantitative structure–activity relationship (3D-QSAR)—using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best CoMFA and CoMSIA models were obtained using the atom-based alignment of 33 compounds, 22 training compounds and 11 tested compounds, and these give desirable statistics; those for the CoMFA standard model were: r _cv² = 0.691, r ² = 0.998, S _press = 0.178, s = 0.014 and F = 1080.765, while CoMSIA combined steric, electrostatic, hydrophobic and hydrogen-bond acceptor fields: r _cv² = 0.600, r ² = 0.988, S _press = 0.206, s = 0.034 and F = 284.433. The 3D-QSAR models calculated satisfactory test set activities. The 3D-QSAR contour plots correlated strongly with the experimental data for the binding topology. For this reason, these results would be beneficial for predicting affinities with the compounds of interest, and they are advantageous for guiding the design and synthesis of new and more effective anticancer agents.     

A new mathematical formula to link near equilibrium relaxation kinetics and conformational selection steps in enzymatic reactions

A new mathematical formula was derived for near equilibrium relaxation processes of enzyme reactions including the conformational selection (CS) modes. CS is one of the most accepted molecular recognition mechanisms, in which protein conformers (CS conformers) are in an equilibrium with varying degrees of ligand binding affinity so that ligands select a particular conformer among them to bind. Using computer simulation techniques, our previous study (Egawa and Callender in Math Biosci 313: 61–70, 2019) predicted that the rate constant for the near equilibrium relaxation processes (k_NER) and the concentration-sum of substrate and product (C_L^t) of enzyme reactions uniquely related to the presence of CS steps in a manner that 1/k_NER versus C_L^t plot transformed from linear to quadratic as the elementary rate constants of inter-conversions among the CS conformers were becoming smaller relative to the rate constants at other steps of the enzymatic reaction system. Thus our previous work could provide a potential tool to detect the presence of CS steps in an enzyme reaction simply by assays using only trace amount of enzyme samples, although logical basis to have the quadratic deformation in the 1/k_NER versus C_L^t plot in response to the presence of CS steps could not be clarified. Employing mathematical approaches that were alternative to those in our previous study, this study succeeded in deriving a theoretical equation that fully explained why and how the CS modes caused the quadratic characters in the 1/k_NER versus C_L^t plot.

     

Conformational dependence of the intrinsic acidity of the aspartic acid residue sidechain in N-acetyl- -aspartic acid-N′-methylamide

The sidechain conformational potential energy hypersurfaces (PEHS) for the γ_L, β_L, α_L, and α_D backbone conformations of N-acetyl- -aspartate-N′-methylamide were generated. Of the 81 possible conformers initially expected for the aspartate residue, only seven were found after geometric optimizations at the B3LYP/6-31G(d) level of theory. No stable conformers could be located in the δ_L, _L, γ_D, δ_D, and _D backbone conformations. The ‘adiabatic’ deprotonation energies for the endo and exo forms of N-acetyl- -aspartic acid-N′-methylamide were calculated by comparing their optimized relative energies against those found for the seven stable conformers of N-acetyl- -aspartate-N′-methylamide. Sidechain conformational PEHSs were also generated for the estimation of ‘vertical’ deprotonation energies for both endo and exo forms of N-acetyl- -aspartic acid-N′-methylamide. All backbone–sidechain (N–H⁻O–C) and backbone–backbone (N–HO=C) hydrogen bond interactions were analyzed. A total of two backbone–backbone and four backbone–sidechain interactions were found for N-acetyl- -aspartate-N′-methylamide. The deprotonated sidechain of N-acetyl- -aspartate-N′-methylamide may allow the aspartyl residue to form strong hydrogen bond interactions (since it is negatively charged) which may be significant in such processes as protein–ligand recognition and ligand binding. As a primary example, the molecular geometry of the aspartyl residue may be important in peptide folding, such as that in the RGD tripeptide.     

The use of MM/QM calculations of 13C and 15N chemical shifts in the conformational analysis of alkyl substituted anilines

The calculation of the ¹³C and ¹⁵N NMR chemical shifts by a combined molecular mechanics (Pcmodel 9.1/MMFF94) and ab initio (GIAO (B3LYP/DFT, 6-31 + G(d)) procedure is used to investigate the conformations of a variety of alkyl substituted anilines. The ¹³C shifts are obtained from the GIAO isotropic shielding (Ciso) with separate references for sp³ and sp² carbons (δc = δref − Ciso). The ¹⁵N shifts are obtained similarly from the GIAO isotropic shielding (Niso) with reference to the ¹⁵N chemical shift of aniline. Comparison of the observed and calculated shifts provides information on the molecular conformations. Aniline and the 2,6-dialkylanilines exist with a rapidly inverting symmetric pyramidal nitrogen atom. The 2-alkylanilines have similar conformations with the NH₂ group tilted away from the 2-alkyl substituent. The N,N-dialkylanilines show more varied conformations. N,N-dimethylaniline has a similar structure to aniline, but N-ethyl, N-methylaniline, N,N-diethylaniline, and N,N-diisopropylaniline are conformationally mobile with two rapidly interconverting conformers. In contrast, the anilines substituted at C₂ and the nitrogen atom exist as one conformer where the steric interaction between the C₂ substituent and the N substituent determines the conformation. In 2-methyl-N-methylaniline, the nitrogen atom is pyramidal as usual with the N-methyl opposite to the 2-methyl, but in 2-methyl-N,N-dimethyl aniline, the NMe₂ group is now almost orthogonal to the phenyl plane. This is also the case with 2-methyl-N,N-diethylaniline and 2,6-diisopropyl-N,N-dimethylaniline. The comparison of the observed and calculated ¹⁵N chemical shifts confirms the above findings, in particular the pyramidal conformation of aniline and the above observations with respect to the conformations of the N,N-dialkylanilines.