Georges Dive

A quasi-Newton algorithm for first-order saddle-point location

SummaryA new algorithm for the location of a transition-state structure on an energy hypersurface is proposed. The method is compared to three other quasi-Newton step calculations available in literature. Numerical results derived from several examples are compared to those obtained by the two algorithms implemented in the Gaussian package.

Coumarinic derivatives as mechanism-based inhibitors of α-chymotrypsin and human leukocyte elastase

Novel coumarinic derivatives were synthesized and tested for their inhibitory potency toward alpha-CT and HLE. Cycloalkyl esters and amides were found to be essentially inactive on both enzymes. On the opposite, aromatic esters strongly inactivated alpha-CT whereas HLE was less efficiently inhibited with dichlorophenyl ester derivatives (kinact/K(I) = 4000 M(-1) s(-1) for 36). Representative examples of amide, ester, thioester and ketone derivatives were prepared in order to evaluate the influence of the link between the coumarinic ring and the phenyl side chain. The irreversible inactivation of alpha-CT by 6-chloromethyl derivatives should be due to alkylation of a histidine residue as suggested by the amino acid analysis of the modified chymotrypsin. Conversely the inhibition of HLE was transient. Intrinsic reactivity of coumarins has been calculated using a model of a nucleophilic reaction between the ligand and the couple methanol-water. From this calculation, it appears that differences in the inhibitory potency expressed by these molecules cannot only be explained by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack.

Biochemistry of the penicilloyl serine transferases

Publisher Summary This chapter discusses the biochemistry of the penicilloyl serine transferases. The penicilloyl serine transferases catalyze cleavage of the cyclic amide bond of penicillin via formation of a serine S* ester-linked penicilloyl enzyme. A mechanistic model of the putative peptidase ancestor is provided by the DD-transpeptidase/PBP of Streptomyces K15. Upon cleavage of the signal peptide of the precursor, the exported 262 amino acid residue protein remains in interaction with the outer face of the membrane. The enzyme consists of one catalytic module. The enzyme has been overexpressed and crystallized in a form suitable for X-ray analysis. Features of evolution also resulted in the emergence of distinct classes of DD-peptidases/PBPs, and β-lactamases. Enzymes belonging to a given class are related in their primary structures by similarity scores which are at least five standard deviations above that expected for a run of twenty randomized pairs of proteins having the same amino acid compositions as the pairs of enzymes under comparison.

Molecular modeling study of β- and γ-cyclodextrin complexes with miconazole

Abstract Different authors have demonstrated the inclusion of miconazole in cyclodextrins (CD). Miconazole can be included in the CD cavity both in the neutral and in the ionized form. The present study tries to understand which fragment of the miconazole molecule is involved in the inclusion. Austin Model 1 approximate molecular orbital calculations have been performed on several complexes between β-cyclodextrin (βCD) or γ-cyclodextrin (γCD) and miconazole in the ionized and the non-ionized forms of the two R and S enantiomers in three different orientations. We observed that βCD is a good vehicle to transport miconazole which can be very easily released. The complexation energy between miconazole and βCD is not very high but the entropic factor has a great incidence on the stability of the formed complex. The inclusion of the dichlorobenzene–CH2–O– and of the imidazole part of the S isomer gives rise to the most probable complex in acidic conditions (ionized miconazole). Nevertheless, the inclusion should be considered as a dynamic process in which different parts of the molecule could be alternatively included in βCD. The present work demonstrates the high capability of deformation of βCD which could easily accommodate several types of ligand. By opposite, the cycle extension in γCD leads to a more rigid vehicle with regards to miconazole.

Synthesis and evaluation of RGD peptidomimetics aimed at surface bioderivatization of polymer substrates.

Several RGD peptidomimetics have been prepared, in a convergent way, from the common ortho-aminotyrosine template (O-substituted with an anchorage-arm or a methyl group, and alpha N-substituted with a fluorine tag for XPS analysis), and various omega-aminoacid derivatives. The most flexible compounds have shown a biological activity similar to that of the peptide reference (RGDS) in the platelet aggregation test. The compound 16a could be fitted (by modelisation) with DMP 728 and c(RGDfV), two cyclic peptides that are good ligands of integrins. The compound 16b has been covalently fixed on the surface of a poly(ethylene terephthalate) membrane used as support for mammalian cell cultivation.

Imidazolopyrazinones as potential antioxidants

A series of imidazolopyrazinones 3, substituted at C-2, and C-2/C-6, has been prepared. The compounds behaved as quenchers of superoxide anion. The more active compounds are structurally related to coelenterazine, a natural substrate of marine bioluminescence. Theoretical parameters based on Hartree-Fock instabilities have been examined.

Asymmetric Diels-Alder reactions of a nitroso compound derived from D-bornane-10,2-sultam

Abstract Acylnitroso dienophile 3 derived from D-bornane-10,2-sultam undergoes cycloaddition with high yields and complete facial selectivity to cyclopentadiene and cyclohexadiene. When the nitroso group is attached to the sultam nitrogen, it is no longer reactive in Diels-Alder reactions.

Energy analysis on small to medium sized H-bonded complexes

SummaryDimers (water-methanol, guanine-cytosine) as well as trimers (methanol-water-imidazole, formamide-methylformate-formamide), are studied as H-bonded complexes of increasing complexity. All the investigated conformations have been fully optimized. In particular, it is the first time that all the intra-and intermolecular parameters of the guanine-cytosine complex are left variable. In minimal basis sets, the planar conformation has been found to be a first-order critical point. The minimal basis set MINI-1 has been adapted to provide nearly planar amides. The stability of the complexes is accounted for by four energy components of the same order: the first-order term (electrostatic + exchange), the polarization, the charge transfer and the correlation terms. In the case of the studied trimers, the energy components, apart from the electrostatic one, have been found to be nearly additive.

Combination of capillary electrophoresis, molecular modelling and nuclear magnetic resonance to study the interaction mechanisms between single-isomer anionic cyclodextrin derivatives and basic drug enantiomers in a methanolic background electrolyte

In order to improve our knowledge of the mechanisms of enantiomer recognition pattern in nonaqueous systems, an approach combining nonaqueous CE (NACE), molecular modelling and NMR was undertaken. Bupivacaine and propranolol were selected as model compounds and their interactions with two single-isomer highly charged β-CD derivatives, namely heptakis(2,3-di-O-methyl-6-O-sulfo)-β-CD (HDMS-β-CD) and heptakis(2,3-di-O-acetyl-6-O-sulfo)-β-CD (HDAS-β-CD), were studied. The CD-bupivacaine complexes were evaluated by 2-D Rotating-frame Overhauser Effect SpectroscopY (ROESY) experiments. From these experiments, it can be assumed that inclusion complexes are not formed, whatever the CD derivative used. Molecular modelling was performed at the RHF/MINI-1 or B3LYP/6-31G(d) level. External as well as inclusion type complexes with the alkyl chain of propranolol into both CD cavities were located. Interaction energies calculated for bupivacaine and propranolol correlated with the enantiomer migration order observed in the NACE experiments using both anionic CD derivatives. The interaction of propranolol with HDMS-β-CD or HDAS-β-CD gives rise to a family of external and inclusion complexes in which some are more probably obtained.

Thiaminylated adenine nucleotides. Chemical synthesis, structural characterization and natural occurrence

Thiamine and its three phosphorylated derivatives (mono‐, di‐ and triphosphate) occur naturally in most cells. Recently, we reported the presence of a fourth thiamine derivative, adenosine thiamine triphosphate, produced in Escherichia coli in response to carbon starvation. Here, we show that the chemical synthesis of adenosine thiamine triphosphate leads to another new compound, adenosine thiamine diphosphate, as a side product. The structure of both compounds was confirmed by MS analysis and 1H‐, 13C‐ and 31P‐NMR, and some of their chemical properties were determined. Our results show an upfield shifting of the C‐2 proton of the thiazolium ring in adenosine thiamine derivatives compared with conventional thiamine phosphate derivatives. This modification of the electronic environment of the C‐2 proton might be explained by a through‐space interaction with the adenosine moiety, suggesting U‐shaped folding of adenosine thiamine derivatives. Such a structure in which the C‐2 proton is embedded in a closed conformation can be located using molecular modeling as an energy minimum. In E. coli, adenosine thiamine triphosphate may account for 15% of the total thiamine under energy stress. It is less abundant in eukaryotic organisms, but is consistently found in mammalian tissues and some cell lines. Using HPLC, we show for the first time that adenosine thiamine diphosphate may also occur in small amounts in E. coli and in vertebrate liver. The discovery of two natural thiamine adenine compounds further highlights the complexity and diversity of thiamine biochemistry, which is not restricted to the cofactor role of thiamine diphosphate.