Conformational analysis of beta and gamma lactam antibiotics

in European Journal of Medicinal Chemistry (1991), 26(1), 43-50

Geometry optimization, superimposition searches and conformational analysis carried on several lactam antibiotics show that reactivity with the active-site serine penicillin-binding proteins is related to ... [more ▼]

Geometry optimization, superimposition searches and conformational analysis carried on several lactam antibiotics show that reactivity with the active-site serine penicillin-binding proteins is related to a particular spatial disposition of 2 flanking functional groups - namely a C = O or C-OH on 1 side and a carboxylate on the other - with respect to the central scissile amide bond. Such a binding entity is found in one of the most stable conformers of the tripeptide diacetyl-L-Lys-D-Ala-D-Ala conferring substrate activity, and in benzylpenicillin, cephapyrin, thienamycin, gamma-lactam, the 6-spiro-epoxypenicillin S and in one epimer of lactivicin, conferring inactivating potency. This binding entity generates a particular electronic distribution and the fact that it is conserved in compounds belonging to very different chemical families strongly suggests that it is an important feature required for enzyme recognition. [less ▲]

PAF receptor structure: a hypothesis

in Lipids (1991), 26(12), 1162-1166

Polarization correction to the electrostatic potential at the CNDO and theab initio level. Influence of the basis set expansion

in Theoretica Chimica Acta (1991), 79(2), 141-152

The influence of the basis set on the electrostatic potential corrected for polarization has been studied for H2S, CH3SH and COHCH2SH. The position and deepness of the minima and the height of the barrier ... [more ▼]

The influence of the basis set on the electrostatic potential corrected for polarization has been studied for H2S, CH3SH and COHCH2SH. The position and deepness of the minima and the height of the barrier between symmetric minima is discussed at both the deorthogonalized CNDO/2 and ab initio levels within STO-3G, 3-21G, 4-31G, 6-31G and 6-311G basis sets. The calculation of the electrostatic potential and corrected one using CNDO deorthogonalized coefficients including 3d orbitals has been applied at the first time on sulfur-containing molecules. The influence of polarization and diffuse functions has also been analysed and the incidence of the polarization correction on the relative proton affinity in NH2(CH2)3NHCH3 and in the adenine molecule has been investigated at the CNDO and ab initio levels. At both levels, the relative proton affinity of several basic sites in the same molecule can be qualitatively expressed without inclusion of the polarization correction except in the case of substituted amines. [less ▲]

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

in Tetrahedron, Asymmetry (1991), 2(12), 1173-1176

Electrostatic Potential Maps at the Quantum Chemistry Level of the Active Sites of the Serine Peptidases, Alpha-Chymotrypsin and Subtilisin

in Journal of Theoretical Biology (1990), 145(2), 183-98

The electronic properties of the active-sites of the structurally unrelated serine peptidases, alpha-chymotrypsin and subtilisin, have been expressed in the form of three-dimensional electrostatic ... [more ▼]

The electronic properties of the active-sites of the structurally unrelated serine peptidases, alpha-chymotrypsin and subtilisin, have been expressed in the form of three-dimensional electrostatic potential maps derived from integrals calculated at the quantum chemistry level. As a consequence of the asymmetrical distribution of the secondary structures that occur within a 7 A sphere around the serine of the catalytic triad, the active sites are highly polarized entities and exhibit large dipole moments. One part of the active sites generates a nucleophilic suction-pump. Its isocontour at -10 kcal mol-1 defines an impressive, negatively-charged volume which bears a narrow channel in the immediate vicinity of the active-site serine 195 in alpha-chymotrypsin or 221 in subtilisin. In native alpha-chymotrypsin, there is a perfect complementation between this nucleophilic suction-pump and the positively-charged electrophilic hole that is generated by the backbone NH of Ser 195 and Gly 193. In subtilisin, generation of the complementing electrophilic hole requires binding of a carbonyl donor ligand and may be achieved by rotation of the side-chain amide of Asn 155 towards the backbone NH of Ser 221. Small variations in the atomic co-ordinates of alpha-chymotrypsin used for the calculations, the presence of water molecules in its active site and the occurrence of point mutations in the amino acid sequence of subtilisin have little effects on the shape and characteristics of the electrostatic potential. [less ▲]

Conformational analysis of β and γ-lactam antibiotics

in European Journal of Medicinal Chemistry (1989), 26(1), 43-50

Geometry optimization, superimposition searches and conformational analysis carried on several lactam antibiotics show that reactivity with the active-site serine penicillin-binding proteins is related to ... [more ▼]

Geometry optimization, superimposition searches and conformational analysis carried on several lactam antibiotics show that reactivity with the active-site serine penicillin-binding proteins is related to a particular spatial disposition of 2 flanking functional groups — namely a C=O or C---OH on 1 side and a carboxylate on the other — with respect to the central scissile amide bond. Such a binding entity is found in one of the most stable conformers of the tripeptide diacetyl-Image -Lys-Image -Ala-Image -Ala conferring substrate activity, and in benzylpenicillin, cephapyrin, thienamycin, γ-lactam, the 6-spiro-epoxypenicillin S and in one epimer of lactivicin, conferring inactivating potency. This binding entity generates a particular electronic distribution and the fact that it is conserved in compounds belonging to very different chemical families strongly suggests that it is an important feature required for enzyme recognition. [less ▲]

Numerical computation of the electrostatic interaction energy between methanol and the dyad water-imidazole

in Theoretica Chimica Acta (1989), 76(2), 85-94

The electrostatic interaction energy between methanol and the dyad water-imidazole has been computed numerically at three levels of approximation from 3D grids of the charge density of one partner and the ... [more ▼]

The electrostatic interaction energy between methanol and the dyad water-imidazole has been computed numerically at three levels of approximation from 3D grids of the charge density of one partner and the electrostatic potential of the other. The minimum positions and energy values thus obtained compare well with those calculated analytically. The numerical procedure is especially interesting for the prediction of the stable conformers. [less ▲]

The Active-Site-Serine Penicillin-Recognizing Enzymes as Members of the Streptomyces R61 Dd-Peptidase Family

in Biochemical Journal (1988), 250(2), 313-324

Homology searches and amino acid alignments, using the Streptomyces R61 DD-peptidase/penicillin-binding protein as reference, have been applied to the beta-lactamases of classes A and C, the Oxa-2 beta ... [more ▼]

Homology searches and amino acid alignments, using the Streptomyces R61 DD-peptidase/penicillin-binding protein as reference, have been applied to the beta-lactamases of classes A and C, the Oxa-2 beta-lactamase (considered as the first known member of an additional class D), the low-Mr DD-peptidases/penicillin-binding proteins (protein no. 5 of Escherichia coli and Bacillus subtilis) and penicillin-binding domains of the high-Mr penicillin-binding proteins (PBP1A, PBP1B, PBP2 and PBP3 of E. coli). Though the evolutionary distance may vary considerably, all these penicillin-interactive proteins and domains appear to be members of a single superfamily of active-site-serine enzymes distinct from the classical trypsin or subtilisin families. The amino acid alignments reveal several conserved boxes that consist of strict identities or homologous amino acids. The significance of these boxes is highlighted by the known results of X-ray crystallography, chemical derivatization and site-directed-mutagenesis experiments. [less ▲]

Molecular graphics software on a raster

in Journal of Molecular Graphics (1988), 6(4), 221

Theoretical study of the C-N bond breakage catalyzed by the serine peptidases

in Journal of Molecular Structure : Theochem (1984), 16

The conditions of C---N bond breakage by the serine peptidases have been analysed. A two-way table has been generated where either formamide or protonated formamide serves as minimal model of the scissile ... [more ▼]

The conditions of C---N bond breakage by the serine peptidases have been analysed. A two-way table has been generated where either formamide or protonated formamide serves as minimal model of the scissile C---N bond and where either methanol or the couple CH3O− H+ serves as minimal model of the attacking nucleophile. An addition-elimination reaction is proposed which links the enzyme acylation and deacylation steps. [less ▲]