Computational methods for conformational analysis of unsymmetrical 1,3-diamines: 3-aminotropanes

A comparative study has been performed to evaluate the ability of a range of computational theories to predict the relative basicity and the conformations of diamine systems. Specifically, molecular mechanics (MM3), semiempirical (AM1), and ab initio (Hartree–Fock) methods have been used in the conformational analyses of unprotonated, monoprotonated, and diprotonated 3-aminotropanes, a pair of isomeric 1,3-diamines. Use of the molecular mechanics force field, with the recently determined parameter set for protonated amines, affords results that are in agreement with experimental data, when corrected for water solvent (by setting the dielectric constant to 80). Ab initio and semiempirical calculations, in contrast, give inconsistent and incorrect results. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1371–1378, 1999     

Pyridine-based receptors with high affinity for carbohydrates. Influence of the degree of steric hindrance at pyridine nitrogen on the binding mode

Remarkable changes in the binding affinity and selectivity of pyridine-based receptors toward monosaccharides have been observed when the degree of steric hindrance at pyridine nitrogen atom decreases.     

Computational study on the ring distortions of 1,4-dicyanobenzene in the gas phase and in the crystal

A molecular mechanics software enhanced to perform empirical energy calculations on crystals (KESSHOU) was further developed to handle intermolecular electrostatic interactions as well. The packing of the molecules of 1,4-dicyanobenzene and 1,4-diisocyanobenzene in the crystal was studied. The role of the van der Waals and the electrostatic interactions in the balance of nonbonded atom-atom interactions is analyzed. The packing forces are dominated by van der Waals forces. The electrostatic interactions have higher stabilizing contribution for the dicyano isomer than for the diisocyano form. The dependence of the results on the size of the crystal, the molecular mechanics force field (MM2 vs MM3), and the dielectric constant are also assessed. Ab initio MP2/6–311G** geometries of the isolated molecules are in accordance with the observed benzene ring distortions determined by electron diffraction.     

Conformational analysis and the binding sites of nitrilotriacetamide: A computational study

The conformational analysis of nitrilotriacetamide has been carried out computationally, at both the semi‐empirical AM1 and density functional theory (DFT) (B3LYP/6‐31+G*) levels of theory. The lowest‐energy conformation predicted with the Monte Carlo search method, using the AM1 model, has two amide functionalities aligned on the same side; however, the DFT calculations at B3LYP/6‐31+G* predicted the global minimum with all three acetamide functionalities on the same side in the gas phase. In the aqueous phase, the DFT results predicted the orientations of amides similar to that of the reported crystal structure. The rotation barriers to transition to different low‐energy conformers of nitrilotriacetamide are lower in energy (5.0 kcal/mol) in water. The molecular electrostatic isopotentials (MESP) generated for the selected conformers at DFT level show that the nitrilotriacetamide could interact more effectively with the sodium chloride surface than that of its monomeric unit nitrilomonoacetamide. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

Modelling of the binding site of the human m1 muscarinic receptor: Experimental validation and refinement

Our model of the human m1 muscarinic receptor has been refined on the basis of the recently published projection map of bovine rhodopsin. The refined model has a slightly different helix arrangement, which reveals the presence of an extra hydrophobic pocket located between helices 3, 4 and 5. The interaction of series of agonists and antagonists with the m1 muscarinic receptor has been studied experimentally by site-directed mutagenesis. In order to account for the observed results, three-dimensional models of m1 ligands docked in the target receptor are proposed. Qualitatively, the obtained models are in good agreement with the experimental observations. Agonists and partial agonists have a relatively small size. They can bind to the same region of the receptor using, however, different anchoring receptor residues. Antagonists are usually larger molecules, filling almost completely the same pocket as agonists. They can usually produce much stronger interactions with aromatic residues. Experimental data combined with molecular modelling studies highlight how subtle and diverse receptor–ligand interactions could be.     

Theoretical study of the stability of myrsinone in vacuo and in solution

The stability of various conformers of myrsinone (2,3-dihydroxy-5-undecyl-1,4-benzoquinone) and its tautomer [2,3-dihydroxy-5-(undec-1-ene)-cyclohex-2-ene-1,4-dione] has been studied in vacuo and in solution on model systems with the long alkyl side chains replaced with ethyl and eth-1-ene groups, respectively. Ab initio Hartree–Fock (HF) calculations in vacuo and free-energy calculations either in chloroform or in water solution, in the framework of the polarizable continuum model, have been carried out on the 6-31G* optimized geometries obtained in vacuo and in solution (water or chloroform). The nature of the stationary points found was investigated using normal mode analysis. The energy gap between the two tautomeric forms turns out to be about 1.3 kcal/mol in vacuo and becomes about 0.3 kcal/mol in chloroform solution, whereas in water the second tautomer is favored by about 1.2 kcal/mol. The effect of second-order M?ller–Plesset (MP2) correlation corrections has been considered on both the energy and the geometry of the tautomers in vacuo, whereas in solution only their effect on the energy was taken into account. The contribution to the stability in the gas phase and in solution of the intramolecular hydrogen bonds between the hydroxy hydrogen and the quinonoid oxygen is larger at the MP2 level than at the HF one. The directionality of the hydrogen bonds between the hydroxy groups affects considerably only the stability of the isomer with the exocyclic double bond. The computed chemical shifts for the two tautomers were compared to the experimental ones. In addition the solvation properties of 2,5-dihydroxy-3-ethyl-1,4-benzoquinone and of an ortho-quinonoid system were considered in order to evaluate the effect of the repulsion between vicinal hydroxy or quinonoid groups. Received: 14 September 1999 / Accepted: 3 February 2000 / Published online: 2 May 2000     

Synthesis of macrocyclic 1,1′-biarenol derivatives by the tandem Claisen rearrangement and their binding properties

Crown ether-type macrocycles consisting of an enantiopure biarenol derivative and an oligoethylene glycol were synthesized by the Lewis acid-mediated tandem Claisen rearrangement. This is the first example of the successful application of the tandem Claisen rearrangement to the synthesis of enantiopure macrocyclic biarenol derivatives. The enantiopure macrocyclic biarenols were found to form 1:1 complexes with amino acid salts and to discriminate their chirality.