Norman Bauman

New method for rapid characterization of molecular shapes: applications in drug design

We present a method for the rapid quantitative shape match between two molecules or a molecule and a template, using atom triplets as descriptors. This technique can be used either as a rapid screen preceding the computationally expensive shape-based docking method developed by Kuntz and co-workers or as a stand-alone method to rank compounds in a large database for their fit to a shape template. The merits and limitations of this method are discussed in detail with examples.

Database diversity assessment: New ideas, concepts, and tools

We present some new ideas for characterizing and comparing largechemical databases. The comparison of the contents of large databases is nottrivial since it implies pairwise comparison of hundreds of thousands ofcompounds. We have developed methods for categorizing compounds into groupsor series based on their ring-system content, using precalculatedstructure-based hashcodes. Two large databases can then be compared bysimply comparing their hashcode tables. Furthermore, the number of distinctring-system combinations can be used as an indicator of database diversity.We also present an indepen- dent technique for diversity assessment calledthe ’saturation diversity‘ approach. This method is based on picking as manymutually dissimilar compounds as possible from a database or a subsetthereof. We show that both methods yield similar results. Since the twomethods measure very different properties, this probably says more about theproperties of the databases studied than about the methods.

Studies on Type II Collagen Induced Polyarthritis in Rats. Effect of Complement Depletion

The effect of cobra venom factor on the developing and the established lesion of collagen-induced rat polyarthritis has been examined. In the developing lesion, decomplementation by cobra venom factor results in a delay in the onset of inflammation and a decrease in the radiological parameters of joint destruction. Under the conditions of the decomplementation, antibody titers to collagen are not decreased. In the established lesion, treatment with cobra venom factor has no effect, on either the inflammatory lesion or the various radiological parameters of joint destruction.

A method for automatic generation of novel chemical structures and its potential applications to drug discovery

A novel method for generation of chemical structures of potential pharmaceutical interest is presented. Structures are generated by random combination of known fragments and selected by statistical topological techniques. The power of the method lies in the great profusion of candidates generated together with the extremely high selectivity imposed by the techniques of selection.

Effects of 5-methoxyindole-2-carboxylic acid on carbohydrate metabolism

Abstract The hypoglycemie effect of 5-methoxyindole-2-carboxylic acid (MICA) has been investigated. MICA promotes neither the uptake of glucose or galactose by peripheral tissues nor the oxidation of glucose, and therefore is not insulin-like. Because it does not produce insulin-like effects and because it is active in the alloxanized mouse, it is not an insulin releaser. MICA blocks gluconeogenesis both in vivo and in the perfused liver; it is proposed that MICA causes hypoglycemia by interfering with gluconeogenesis. MICA depletes liver glycogen even in the face of exogenous hyperglycemia.

Computer-based system for correlating molecular structures with mass spectral data Methods for generating molecular substructures and for incorporating fragmentation rules

Abstract The masses of ions observed in the mass spectrum of a pure compound are correlated with the masses of the molecular substructures of the compound. Three methods are described for generating molecular substructures. Each method is evaluated to establish how effectively it generates the molecular substructures and correlates the masses of the molecular substructures with the masses of the observed fragment ions. Rules for mass-spectral fragmentation processes are incorporated into the mass spectral analysis software and illustrated for retro-aldol and lactone-ester reactions occurring in the thermospray mass spectra of oligomycin antibiotics.

Passive transfer of collagen arthritis: Studies with affinity-purified anticollagen IgG prepared in rabbits

Affinity-purified rabbit anticollagen IgG failed to transfer arthritis to rats when it was injected intravenously. Immunofluorescence examination of the joints of the hind paws of recipient rats showed the deposition of rabbit IgG on the articular surfaces; however, C4 or C3 deposition was not detected. In recipient rats injected intravenously with equivalent amounts of rat anticollagen IgG, arthritis occurred within 48 hr; IgG, C4, and C3 could be detected on the articular surface. Rats given Type II collagen intravenously accumulated inflammatory cells in the pleural cavity in response to a subsequent challenge with intrapleural rat anticollagen IgG; with rabbit anticollagen IgG significantly fewer cells accumulated. Rabbit anticollagen IgG did not promote the lysis of Type II collagen coated sheep red blood cells that were incubated with rat serum. In parallel control experiments, lysis of cells occurred when rat serum was added to either sheep cells coated with Type II collagen and incubated with rat anticollagen IgG or sheep cells coated with bovine serum albumin and incubated with rabbit anti-bovine serum albumin. These observations suggest that the failure of rabbit anticollagen IgG to transfer arthritis to rats is, at least in part, due to its inability to activate rat complement.

Systematic discovery and evaluation of complement inhibitors

Methods are presented for an orderly search of a chemical file for complement inhibitors. Compounds are initially examined for intrinsic activity against dilute human components in vitro, using hemolytic assays to detect inhibitors of fluid phase C1, of late components lysis of EAC142, and of CVF-induced passive lysis of AET-treated human erythrocytes. Active compounds are then examined for activity against undiluted serum in vitro. Compounds passing this test are examined for activity in vivo against serum complement and complement-dependent lesions, viz. Forssman vasculitis, the reverse passive Arthus phenomenon, and Forssman shock. Methods are given for quantitation of these lesions.

Effects of iodipamide on human C3 and factor B in vitro

The effects of iodipamide on C3 and factor B in normal human serum and in purified form have been examined by immunoelectrophoresis and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Temperature-dependent changes in immunoelectrophoretic profiles have been observed; however, these are not the same as those obtained after treatment of normal human serum (NHS) with cobra venom factor Naja naja. Analyses of iodipamide-treated NHS and purified C3 and factor B by reducing SDS-PAGE indicate that no macromolecular changes have occurred in C3 and factor B that can be ascribed to proteolysis (i.e., activation). The changes observed in C3 and factor B, including loss of hemolytic activity, appear to be due to direct interactions between iodipamide and C3 and factor B. In the case of factor B, iodipamide treatment at 37 degrees C induces aggregation, which is reversible upon reduction with beta-mercaptoethanol.

The relative efficacies of 7S and 19S Forssman antibody in producing lesions in the guinea pig.

Summary The ability of rabbit antiserum to heated sheep erythrocyte stroma to cause Forssman shock and cutaneous vasculitis in the guinea pig resides in its IgG fraction and not in its IgM fraction, although the latter fixes complement with guinea pig tissue both in vitro and in vivo.