Multi-steady-state model for cell differentiation.
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Cell Differentiation↗
Biomedical subjects
Z Simon
Publications and source records attributed to Z Simon.
Lethal mutation hypothesis for the mechanism of action of the cytostatic alkylating agents.
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Alkylating Agents↗
Quantitative and qualitative approach of glycan-glycan interactions in marine sponges.
Cell recognition and adhesion involving many kinds of cell surface molecules operate via homotypic and/or heterotypic protein-protein and protein-carbohydrate binding. Our investigations in marine sponges have provided direct evidence for a novel molecular mechanism of multivalent glycan-glycan binding related to cellular interactions. Biochemical characterization of purified proteoglycans revealed the presence of specific acidic glycans, different from classical glycosaminoglycans. Such acidic glycans of high molecular weight, containing fucose, glucuronic or galacturonic acids, and pyruvate and sulfate groups may represent a new class of primordial proteoglycans, named by us glyconectins. The thermodynamic and kinetic approaches of biological macromolecule interactions do not provide a direct measurement of the intermolecular binding forces that are fundamental for the function of the ligand-receptor association. Using the atomic force microscopy (AFM), we provided the first quantitative evaluation of the binding strength between cell adhesion proteoglycans. Measurement of binding forces intrinsic to cell adhesion glyconectin proteoglycans (AGPs) is necessary to assess their contribution to the maintenance of the anatomical integrity of multicellular organisms. (i) As a model, we selected the cell AGP isolated from the marine sponge Microciona prolifera; it mediates in vivo cell recognition and aggregation via homotypic, species-specific, multivalent, and calcium ion-dependent glycan-glycan interactions. (ii) Under physiological conditions, a large cohesive force theoretically able to hold the weight of approximately 1600 cells was measured. (iii) The C-2 autocomplementarity model for AGP-AGP interactions; and (iv) the requirement of the calcium ionic bridges suggest also that the self-recognition and multivalency of glycan-glycan interactions are essential for cell adhesion. (v) The evolution of glyconectin-like proteoglycan molecules may have been a fundamental prerequisite for the emergence of the first multicellular organisms. Glycan-glycan interactions may thus provide a new paradigm for molecular self-recognition.
Animals↗
MTD calculations on quantitative structure-activity relationships of steroids binding to the progesterone receptor.
The minimal topological difference (MTD) method is used to describe quantitative structure-activity relationships (QSAR) for the progesterone-receptor binding affinity including 59 progestational steroids. Multiple correlation coefficients of r = 0.962 and r = 0.955 are obtained by use of the MTD variable and a measure of hydrophobicity for the series of progesterone and ethisterone derivatives, respectively. Hydrophobic effects are found to strongly influence receptor binding. In accordance with the hydrogen bonding concept, the optimized MTD receptor maps indicate cavity vertices in the regions of oxygen functions at C3 and in the 17 beta position. Receptor wall vertices are attributed in the areas of 4, 10 beta, and 13 beta substituents of 4-en-3-one steroids while 17 alpha side chains additionally contain receptor cavity vertices. A comparison of corresponding receptor maps suggests in accord with X-ray crystal structure data that progesterone and ethisterone derivatives are bound in somewhat different orientations relative to the receptor surface.
Animals↗
Theoretical investigations on the role of steroid-skeleton C4 = C5 unsaturation in competitive aromatase inhibition.
A quantitative structure-activity relationship (QSAR) approach by use of the minimal topological difference (MTD) method including 46 derivatives of 4-androstene-3,17-dione and 5 alpha-androstane-3,17-dione is applied to give indications about the role of the C4 = C5 double bond in competitive inhibition of human placental aromatase and about sterical requirements in steroid-aromatase interactions. The inhibitory activity is found to correlate with the sterical MTD variable, hydrophobicity, and pi-system conjugation in the A,B-ring region. A comparison of the MTD results reveals a good agreement with interpretations based on free-energy data derived from inhibition constants. By means of MM2 molecular mechanics and PCILO quantum-chemical calculations, the 4-ene structure is shown to significantly influence conformational features of C19 substituents which are important in enzymatic transformations. While 19-hydroxy-5 alpha-androstane-3,17-dione favour a conformation having the hydroxyl group in the enzyme-directed out-of-ring position, the C4 = C5 double bond energetically enables the steroid to adopt a conformation which can be hydroxylated without internal rotations. According to present theoretical findings, the 4-ene unsaturation thus exerts an indirect conformational influence by hydroxyl positioning appropriate to aromatase interactions and a direct electronic influence by pi conjugation.
Androstenedione↗
Influence of drugs and ionic gradients on gastric secretory epithelium in vitro.
The first part of the paper is devoted to the description of the data acquisition system for studies on epithelial membranes using a process-control computer ECAROM connected to the usual two half-chambers device for epithelial transport studies in vitro. The second part presented the results obtained in several types of experiments concerning the effect of drugs (histamine, acetazolamide) and ionic gradients (K+, Cl-, H+) on the potential difference and/or acid secretion rate.
Acetazolamide↗
MTD approach to quantitative structure-activity relationships for cardiotonic steroids.
A minimal topological difference (MTD) approach is made to describe quantitative structure-activity relationships (QSAR) for the Na+, K+-ATPase inhibitory activity of cardiotonic steroids. The calculations take into account 20 derivatives of digitoxigenin, digoxigenin, and gitoxigenin with small substituents at different sites of the steroid backbone. A multiple correlation coefficient of r = 0.916 is obtained using the MTD and an indicator variable for the presence of a 15 beta substituent. The corresponding receptor map reveals receptor wall vertices in the C11, C12, C15, and C22 regions. Both 3 beta and 16 beta substituents are found to contain receptor cavity vertices. The MTD results are discussed with respect to lactone-ring conformational investigations presented and they are compared with findings of previous structure-activity studies.
Cardiac Glycosides↗
[Quantitative structure-activity relations applied to 2 classes of inhibitors of chemical carcinogenesis].
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Animals↗
Minimal steric difference study of structural requirements for the luteinizing hormone-releasing hormone (LH-RH) receptor.
Quantitative structure-activity relation for amino acid substitution analogues of the LH-RH decapeptide were established by means of the receptor site mapping procedure based upon minimal steric differences. For a series of 17 analogues of LH-RH, obtained by substitutions of the C-terminal Gly-NH2 residue, a corelation coefficient r = 0.93 was obtained, for a series of 7 analogues, obtained by substitutions of the Leu7 residue, r = 0.95 was obtained. The shape of the LH-RH receptor regions interacting with the C-terminal of the decapetide and with the Leu7-side chain is inferred from this study.
Binding Sites↗
Molecular aspects concerning antigen oligopeptide selection by MHC class I molecules.
T cells can recognize the antigen only if it is associated with self MHC molecules on the surface of antigen presenting cells (APC). There are several characteristic parameters defining interaction of MHC molecule with antigenic peptides giving circumstances for specific antigen presentation and an individualized immune response. Here are assessed some size and conformational parameters of the peptides presented by MHC class I molecules-lengths, widths, van der Waals volumes and surfaces-using COSMIC 2.0 software. The peptides derived from HIV gp 160 are obtained from literature and are known to be active and inactive in a cytotoxicity assay. An increased tendency for beta- or beta-like structures and volumes close to those of the MHC binding site are encountered in the case of active peptides.
Amino Acid Sequence↗
Quantitative structure-activity relations by the MTD-method for binding of nonapeptides to the HLA-A2.1 molecule.
Binding of large series of nonapeptides to the HLA-A2.1 molecule was studied by a group of Sette in order to predict strongly binding peptides with possible therapeutic interest. Here we establish QSAR-s for these series. The MTD-method was used for steric requirements concerning amino acidic side chains as well as side chain hydrophobicities. Binding of these peptides to the HLA-A2.1 molecule is favored by a lipophylic character of side chains for the anchor position 2 and 9 and for positions 1,3 and 6 and by steric features that allow predictions for some modified amino acidic residues in these positions that should increase the peptide-HLA-molecule affinity.
Amino Acids↗