2,7-dihydroapogeissoschizine from root bark of strychnos Gossweileri

in Phytochemistry (1994), 35(2), 533-536

Detailed Study of a Molecule in a Molecule N-Acetyl-L-Tryptophanamide in a Active-Site Model of Alpha-Chymotrypsin

in Journal of the American Chemical Society (1994), 116(6), 2548-2556

Six complexes between a model active site of alpha-chymotrypsin (261 atoms) and N-acetyl-L-tryptophanamide (33 atoms) were optimized at the semiempirical AM1 level. In one of these complexes, a water ... [more ▼]

Six complexes between a model active site of alpha-chymotrypsin (261 atoms) and N-acetyl-L-tryptophanamide (33 atoms) were optimized at the semiempirical AM1 level. In one of these complexes, a water molecule was included. A detailed study at the geometric and energetic levels is presented. The discussion deals with the nature of the interaction, the effect of the environment, the ligand deformation, the backbone relaxation, the water molecule freedom, and the comparison with the molecular mechanics results. [less ▲]

Analytical calculation of the electrostatic interaction energy within the CNDO framework

in International Journal of Quantum Chemistry (1993), 46(6), 711-734

This work analyses the adequacy of an analytical electrostatic energy formulation within the CNDO framework to predict the stable conformations of large molecular complexes. Comparisons are made with ab ... [more ▼]

This work analyses the adequacy of an analytical electrostatic energy formulation within the CNDO framework to predict the stable conformations of large molecular complexes. Comparisons are made with ab initio results for small systems such as water-formamide, methanol-water-imidazole, or guanine-cytosine and with AM1 results for two large systems: a molecular tweezer + the 9-methyladenine complex and a model active site of the alpha-chymotrypsin and its ligand complex. This approach is efficient in providing reliable conformers for large molecular systems in a very fast way. [less ▲]

Design and modeling of new platelet-activating-factor antagonists.1. Synthesis and biological activity of 1,4-bis(3',4',5'-trimethoxybenzoyl)-2-[[(substituted carbonyl and carbamoyl)oxy]methyl]piperazines

in Journal of Medicinal Chemistry (1993), 36(8), 990-1000

A VARIABLE MECHANISM FOR THE NUCLEOPHILIC VINYLIC SUBSTITUTIONS IN A SERIES OF GEM-DIHALOGENATED ALKENES BY A BIDENTATE SULFUR NUCLEOPHILE - AN EXPERIMENTAL AND AM1 THEORETICAL-STUDY

in Journal of Organic Chemistry (1993), 58(17), 4685-4690

The nucleophilic substitutions of a series of gem-dihalogenated alkenes 3,5,7,8, and 9 (RS)2C=CX2 (X = Cl, F) with 1,2-benzenedithiolate b have been studied. Depending on the structures of the R groups ... [more ▼]

The nucleophilic substitutions of a series of gem-dihalogenated alkenes 3,5,7,8, and 9 (RS)2C=CX2 (X = Cl, F) with 1,2-benzenedithiolate b have been studied. Depending on the structures of the R groups (alkyl, saturated and unsaturated cycloalkyls, aromatic ring), the course of the reactions and the structures of the yielded products are modified. In the frame of the addition-elimination-type mechanism for these nucleophilic substitutions, the energy contents of the anionic intermediates, resulting from the additions of the nucleophile b to the unsaturated centers, is calculated at the AM1 method level. For the compounds 5, 7, 8, and 9, the calculated energies nicely corroborate the experimental results. For 3, anionic intermediates are no longer found by calculation, and a synchronous single-step substitution is strongly suggested. [less ▲]

Polarization correction of the electrostatic potential for aromatic-compounds - Study of the nucleophilic-attack

in International Journal of Quantum Chemistry (1993), 46(1), 127-136

The electrostatic potential (EP) and the polarization correction (PL) on the EP were calculated for four aromatic compounds: benzene, chlorobenzene, phenol, and benzoic amide, at the ab initio SCF level ... [more ▼]

The electrostatic potential (EP) and the polarization correction (PL) on the EP were calculated for four aromatic compounds: benzene, chlorobenzene, phenol, and benzoic amide, at the ab initio SCF level within two basis sets: 6-31G** and MINI-1. One calculation was performed using the polarized MINI-1** basis set. The quantity total interaction energy (TEH) defined as -EP + PL can be used as an indicator of the nucleophilic attack preferential position. By reference to 6-31G**, MINI-I provides very satisfactory results. Moreover, the MINI-1** results are very similar to the MINI-I ones. It appears that -EP does not provide a reliable tool to study the nucleophilic attack susceptibility, whereas TEH seems to be very well adapted for this kind of approach. [less ▲]

Streptomyces Albus G Serine Beta-Lactamase. Probing of the Catalytic Mechanism Via Molecular Modelling of Mutant Enzymes

in Biochemical Journal (1992), 282(Pt 1), 189-195

In previous studies, several amino acids of the active site of class A , β-lactamases have been modified by site-directed mutagenesis. On the basis of the catalytic mechanism proposed for the Streptomyces ... [more ▼]

In previous studies, several amino acids of the active site of class A , β-lactamases have been modified by site-directed mutagenesis. On the basis of the catalytic mechanism proposed for the Streptomyces albus G , β-lactamase [Lamotte- Brasseur, Dive, Dideberg, Charlier, Frere & Ghuysen (1991) Biochem. J. 279, 213-221], the influence that these mutations exert on the hydrogen-bonding network of the active site has been analysed by molecular mechanics. The results satisfactorily explain the effects of the mutations on the kinetic parameters of the enzyme's activity towards a set of substrates. The present study also shows that, upon binding a properly structured ,β-lactam compound, the impaired cavity of a mutant enzyme can readopt a functional hydrogen-bonding-network configuration. [less ▲]

Influence of the Counterpoise Correction on the Optimized Relativi Degrees of Freedom in the H-Bonded Complex Water-Formamide

in Theoretica Chimica Acta (1992), 81(4-5), 281-290

The correction of the basis set superposition error by the counterpoise method has been investigated at the SCF level for the weak H-bonded water-formamide complex and the results have been compared with ... [more ▼]

The correction of the basis set superposition error by the counterpoise method has been investigated at the SCF level for the weak H-bonded water-formamide complex and the results have been compared with the uncorrected results at the SCF, post SCF and semi-empirical AM1 and MNDO levels. Our particular concern has been the determination of the three optimized relative degrees of freedom and the relative stability of three C(s) geometrical conformations. The conclusions are that the counterpoise correction weakly conditions the variation in the degrees of freedom and the relative stabilities of the three conformers. The correction is obviously inadequate to describe intramolecular deformation. [less ▲]

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

in Theoretica Chimica Acta (1992), 82

A 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 ... [more ▼]

A 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. [less ▲]

Mechanism of Acyl Transfer by the Class a Serine Beta-Lactamase of Streptomyces Albus G

in Biochemical Journal (1991), 279(Pt 1), 213-221

Optimization by energy minimization of stable complexes occurring along the pathway of hydrolysis of benzylpenicillin and cephalosporin C by the Streptomyces albus G beta-lactamase has highlighted a ... [more ▼]

Optimization by energy minimization of stable complexes occurring along the pathway of hydrolysis of benzylpenicillin and cephalosporin C by the Streptomyces albus G beta-lactamase has highlighted a proton shuttle that may explain the catalytic mechanism of the beta-lactamases of class A. Five residues, S70, S130, N132, T235 and A237, are involved in ligand binding. The gamma-OH group of T235 and, in the case of benzylpenicillin, the gamma-OH group of S130 interact with the carboxylate group, on one side of the ligand molecule. The side-chain NH2 group of N132 and the carbonyl backbone of A237 interact with the exocyclic CONH amide bond, on the other side of the ligand. The backbone NH groups of S70 and A237 polarize the carbonyl group of the scissile beta-lactam amide bond. Four residues, S70, K73, S130 and E166, and two water molecules, W1 and W2, perform hydrolysis of the bound beta-lactam compound. E166, via W1, abstracts the proton from the gamma-OH group of S70. While losing its proton, the O-gamma atom of S70 attacks the carbonyl carbon atom of the beta-lactam ring and, concomitantly, the proton is delivered back to the adjacent nitrogen atom via W2, K73 and S130, thus achieving formation of the acyl-enzyme. Subsequently, E166 abstracts a proton from W1. While losing its proton, W1 attacks the carbonyl carbon atom of the S70 ester-linked acyl-enzyme and, concomitantly, re-entry of a water molecule W'1 replacing W1 allows E166 to deliver the proton back to the same carbonyl carbon atom, thus achieving hydrolysis of the beta-lactam compound and enzyme recovery. The model well explains the differences found in the kcat. values for hydrolysis of benzylpenicillin and cephalosporin C by the Streptomyces albus G beta-lactamase. It also explains the effects caused by site-directed mutagenesis of the Bacillus cereus beta-lactamase I [Gibson, Christensen [less ▲]