Consensus molecular alignment based on generalized procrustes analysis.

One of the most serious problems in three-dimensional quantitative structure-activity relationship (3D-QSAR) studies is selection of an alignment rule for molecular super position of the compounds in the data set. In 3D-QSAR analyses of structure-activity data, a reference compound in a defined conformation is chosen, and all structures in the data set are aligned with the reference in a pairwise manner. In subsequent steps, conformation/alignment-dependent descriptors are computed for the compounds and compared to those of the reference. This approach gives much weight to the arbitrarily chosen reference molecule and can introduce a bias in the results. Here an alternative, and more general, approach to molecular alignment is presented that is based on Generalized Procrustes Analysis (GPA). The result is a consensus alignment that uses all molecules in the data set and avoids the bias introduced in the pairwise alignment strategy.

Comparison of shear and flexural bond strength tests versus failure modes of dentin bonding systems.

PURPOSE: To (1) measure the shear and flexural bond strengths of three different bonding agents that use different application techniques, (2) determine whether the shear and flexural bond tests rank the three materials similarly, and (3) determine whether the fractured surface produced with the flexural test, facilitates studies of failures within the adhesive interphase region. MATERIALS AND METHODS: Scotchbond MP (SBMP), Single Bond (SNGB) and Clearfil SE (CLSE) were evaluated. For each material, 16 samples were bonded. Eight of these samples were bonded for shear testing and the other 8 samples for flexural bond strength testing. After the bonding was completed, all samples were stored in water at 37 degrees C for 30 days. Shear bond strength was measured using an orthodontic edge wire loop and flexural strength was measured using a 4-point bending device. The samples used for the flexural test consisted of 3 mm x 3 mm x 20 mm beams in which center a 1 mm thick dentin wafer had been bonded perpendicularly to the length of the beam. An indentation with a microhardness tester was placed at one of the dentin-composite interfaces to serve as an induced flaw. This flaw was placed on the surface in tension during flexural testing. The data were analyzed using ANOVA. Scanning electron microscopy was used to examine each specimen and assign its failure mode. Percent occurrence of failure mode was determined for each material and overall for both test methods. When there was uncertainty regarding failure location, electron dispersive spectroscopy x-ray analysis was used to identify elements present on the fractured surface. RESULTS: No significant difference (P > 0.05) in bond strength was observed within each test group, while significant differences (P < 0.05) existed between the two test methods (shear: SBMP = 21.2 +/- 4.0 MPa, SNGB= 24.3 +/- 4.7 MPa, CLSE= 24.6 +/- 4.4 MPa; flexural strength: SBMP= 34.6 +/- 9.3 MPa, SNGB = 31.9 +/- 6.9 MPa, CLSE= 34.3 +/- 4.7 MPa). Shear bond test specimens failed mostly within dentin (54.2%), followed by failures within the adhesive interphase (41.6%), and failures in composite (4.2%). Flexural strength specimens failed mostly within the adhesive interphase (83.3%), followed by failure in composite (16.7%). Bond strengths were similar for all three adhesive systems within each test method group. Failure mode analysis revealed significant differences (P < 0.0001) among the two test methods.

Synthesis and opiate receptor binding properties of 17-methyl-6,7-dehydro-3,14-dihydroxy-4,5alpha-epoxy-6,7:4',5'-pyrimidin omorphinans.

A class of opioid receptor active derivatives of oxymorphone has been synthesized using a common enaminone intermediate. The derivatives have heterocyclic groups fused to the 6,7-positions of the morphinan system and all were synthesized in high yield. A pyrazolo derivative is an agonist for the mu and delta receptors and an antagonist for the kappa receptor.

Effects of some 7-arylidene and 7-heteroarylidene morphinan-6-ones on the antinociceptive activity of [D-Pen2, D-Pen5]enkephalin and [D-Ala2, Glu4]deltorphin II and on multiple opioid receptors.

The in vivo and functional effects of several 7-arylidene and 7-heteroarylidene morphinan-6-ones were determined at the mu-, delta-, and kappa-opioid receptors using the guinea pig brain membranes, guinea pig ileum (GPI), and mouse vas deferens (MVD). In vivo effects included the antagonism by these compounds given subcutaneously on the antinociceptive actions of intracerebroventricularly injected [D-Pen2, D-Pen5]enkephalin (DPDPE) and [D-Ala2, Glu4]deltorphin II (deltorphin II), the highly selective putative delta 1- and delta 2-opioid receptor agonists. Finally, the partition coefficients of these compounds were estimated (CLOGP) and determined experimentally at pH 7.4 in the 1-octanol/water system. Compared with E-7-benzylidenenaltrexone (BNTX), most compounds except for E-7-(4-chlorobenzylidene)naltrexone, were more potent at delta-opioid receptors than at the mu-opioid receptor, whereas, in comparison to the kappa-opioid receptor, the activities of the E-7-arylidene or E-7-heteroarylidene naltrexone derivatives at the delta-receptor were in the following order, where the 7-substituents were: 4-fluorobenzylidene- > benzylidene > 3-pyridylmethylene- > 4-pyridylmethylene- > 1-methyl-2-imidazolylmethylene > 4-chlorobenzylidene. In the MVD preparation, the potencies at the delta-opioid receptor, in comparison to BNTX, were in the following order, where the 7-substituents were: benzylidene = 1-methyl-2-imidazolylmethylene- > 4-fluorobenzylidene- = 3-pyridylmethylene- = 4-pyridylmethylene-. All compounds antagonized delta 1, and delta 2-opioid receptor agonist-induced analgesia. The antagonist potencies at the delta 1-opioid receptor were in the following order, where the 7-substituents were: benzylidene- > 4-chlorobenzylidene- > 4-fluorobenzylidene- > 3-pyridylmethylene- > 1-methyl-2-imidazolymethylene- approximately 4-pyridylmethylene-, whereas at the delta 2-opioid receptor, the order was benzylidene- > 4-chlorobenzylidene- > 4-fluorobenzylidene- > 3-pyridylmethylene- > 1-methyl-2-imidazolymethylene- > 4-pyridylmethylene. In general, all compounds exhibited greater potency at the delta 2- than delta 1-opioid receptor. The computed partition coefficients were, as expected, greater than the apparent log P values, which were determined experimentally. Generally, the lipophilicity values in decreasing order were: 4-chlorobenzylidene- > 4-fluorobenzylidene- > benzylidene > 3-pyridylmethylene- = 4-pyridylmethylene- > 1-methyl-2-imidazolylmethylene-. In general, the benzylidene and 4-pyridylmethylene derivatives, which have medium lipophilicities, were equally effective at the delta 1- and delta 2-receptors; the 3-pyridylmethylene and 1-methyl-2-imidazolylmethylene derivatives had lower lipophilicities and were more selective for the delta 2- than delta 1-receptor; the 4-chlorobenzylidene and 4-fluorobenzylidene derivatives were more lipophilic and had intermediate activity. The plot of pED50 values for the in vivo tests for the delta 1- and delta 2-receptors showed that the two receptors are not independent with respect to this series of compounds.

Solution of the conformation and alignment tensors for the binding of trimethoprim and its analogs to dihydrofolate reductase: 3D-quantitative structure-activity relationship study using molecular shape analysis, 3-way partial least-squares regression, and 3-way factor analysis.

Molecular recognition is the basis of rational drug design, and for this reason it has been extensively studied. However, the process by which a ligand recognizes and binds to its receptor is complex and not well understood. For the case in which the geometries (conformation and alignment) of the ligand and receptor are known from X-ray crystal structure data, the problem is simplified. The receptor-bound conformation and alignment of the ligand is assumed, and those of additional ligands are inferred. For the general case in which the geometries of the ligand(s) and receptor are unknown, no general treatment or solution is available and receptor-ligand geometries must be obtained indirectly from structure-activity studies or synthesis and evaluation of rigid analogs. A general treatment for solving for the receptor-bound geometry of a series of ligands is presented here. Using molecular shape analysis, for ligand description, tensor analysis of N-way arrays by partial least-squares (PLS) regression, and 3-way factor analysis, the receptor-bound geometries of trimethoprim and a series of trimethoprim-like dihydrofolate reductase inhibitors are correctly predicted.

Esthetics: patients' perceptions of dental attractiveness.

PURPOSE: The importance of dentofacial attractiveness to the psychosocial well-being of an individual has been well established. Very little information is available regarding dental patient perceptions of a pleasing esthetic image. The purpose of this study was to identify factors distinctive to attractive smiles versus unattractive smiles, as perceived by patients. MATERIALS AND METHODS: Standardized format photographs (5 x 7 in, matte finish, at f-32 and 1:2 magnification) of eight male and eight female smiles, framing only lips and teeth, were viewed by 297 subjects. The smiles exhibited differences in symmetry, tooth shade, number of teeth displayed, and height of maxillary lip line, and included both restored and unrestored teeth. Respondents ranked the photographs in order from most to least appealing appearance. Respondents viewed each series of photographs in a similar lighting and time period. A questionnaire identified the respondent's age, sex, race, education, income, and home town. Twenty-five demographic groups were established from the information in the questionnaire. Data were analyzed using stepwise discriminant analysis to determine the combination of smile characteristics that best predicted the ranking. RESULTS: The same female smile was chosen as the most attractive by 24 of the 25 demographic groups. This smile is characterized by natural teeth having light shade, high lip line, a large display of teeth, and radiating symmetry. Two female smiles typified by darker shade and asymmetry were rated by all groups as being least attractive. Two male smiles were judged equal as the most pleasing esthetically. Respondents favored those smiles characterized by light shade, a moderate display of teeth, moderate lip line, and a symmetrical arrangement of teeth. One male smile characterized by darker shade was rated as least attractive. CONCLUSIONS: In all cases, tooth shade was the most important factor, followed in sequence by unrestored natural teeth and number of teeth displayed. No correlation was found to exist between specific demographic groups and smile variables.

Amino acid side chain descriptors for quantitative structure-activity relationship studies of peptide analogues.

This report describes a new set of amino acid side chain descriptors, the isotropic surface area (ISA), and the electronic charge index (ECI) relevant to peptide quantitative structure--activity relationship (QSAR) studies. These features are derived from optimized three-dimensional structures of the natural and unnatural amino acids. Since the descriptors are derived considering side chain three-dimensional structure, 3D-QSARs result. Using the method of partial least squares, 3D-QSARs of peptide sets were developed. A comparison of the results to those obtained with the principal properties or z-scales shows that the ISA and ECI are comparable for parameterizing the structural variability of the peptide series and represent an interesting alternative.

A generalized formalism of three-dimensional quantitative structure-property relationship analysis for flexible molecules using tensor representation.

A general formalism, based upon tensor representation of multidimensional data blocks, is presented to express relationships between dependent properties and independent molecular feature measures. The solutions to these data set problems are three-dimensional quantitative structure-property relationships, 3D-QSPRs. The molecular features are partitioned into the intrinsic molecular shape tensor, the molecular field tensor, a nonshape/field feature tensor, and an experimental feature tensor. The intrinsic molecular shape tensor contains information on the shape of a molecule within the contact surface while the molecular field tensor contains information outside of the contact surface. Molecular features not directly related to molecular shape are put into the nonshape/field tensor. Experimental measures not being used as dependent variables can be considered as independent molecular features in the experimental feature tensor. The 3D-QSPR is realized by constructing the transformation tensor which optimizes the statistical significance between the dependent and independent variables. Use of partial least squares (PLS) regression permits the unfolding of the composite feature tensor and the identification of the optimum transformation tensor. It is pointed out that a variety of fragment, whole-molecule, two-dimensional, and/or three-dimensional features can be placed into a nonshape/field tensor.

Construction of a molecular shape analysis-three-dimensional quantitative structure-analysis relationship for an analog series of pyridobenzodiazepinone inhibitors of muscarinic 2 and 3 receptors.

A generalized three-dimensional (3D) quantitative structure-property relationship (QSPR) formalism, based upon molecular shape analysis (MSA), has been applied to an analog series of pyridobenzodiazepinone inhibitors of muscarinic 2 (M2) and 3 (M3) receptors. The fundamental goal of this application is to establish MSA-3D-QSARs (P = A = inhibition activity) that are based upon identifying the active conformations of these flexible analogs. The repetitive use of partial least squares (PLS) analysis permits the construction of the MSA-3D-QSARs. In addition to molecular shape, the identification of the properties of a lipophilic binding site and specific nonallowed steric receptor sites govern the MSA-3D-QSARs. The M2 and M3 QSARs suggest receptor subtype specificity might be realized by targeting upon a specific nonallowed steric receptor site. One conformation, common to both M2 and M3 receptors, emerges as dominant in the optimum MSA-3D-QSARs. However, other similar conformations are also found to yield meaningful MSA-3D-QSARs.

A critical view of the rationale for routine, initial and periodic radiographic surveys.

Most dentists and dental faculties use an initial radiographic survey for the comprehensive-care patient rather than selective radiography, as recommended by professional organizations and radiation protection agencies. Survey or screening radiography has been justified in the belief that it is an essential health service designed to disclose serious occult disease and that failure to use such films might expose the dentist to successful malpractice litigation. However, incidence data indicate the chance of disclosing tumors, non-inflammatory cysts or other serious bone disease in the asymptomatic patient by screening jaw films is infinitesimal. On this basis, the practice is not justifiable as a public health measure, nor is the dentist who follows published national guidelines for prescription radiography vulnerable to successful litigation.

Relationship between partitioning properties and (calculated) molecular surface. SPR investigation of imidazoquinazolone derivatives.

Structure-property relationship (SPR) investigations have been carried out for a series of N-bridged compounds synthetized recently as potential antithrombotic agents. The octanol/water partition coefficient and reversed phase HPLC retention (log k') were determined experimentally for ten imidazoquinazolone derivatives. Calculations including total geometry optimization and surface area have been carried out. The isotropic surface area (ISA) of supermolecules were obtained. The good correlations were found between log P, log k' and ISA values, provide simple and reliable means by using a single structural parameter for the log P prediction of polycyclic N-bridged compounds.

QSAR approaches to predicting toxicity.

Due to the demands of time and the high cost of testing compounds for toxicity in test animals, it would be an advantage to be able to estimate the toxic response of chemical agents using theoretical approaches. Predicting whether a compound will be toxic or nontoxic is a classification problem and the methods of studying quantitative structure activity relationships (QSAR) can be used for this purpose [Hansch, C. (1969) Accounts Chem. Res., 2, 232]. It should be recognized, however, that formulating the QSAR problem as one of active vs. inactive makes it different from classical QSAR problems. This requires that methods be applied that can predict the category of a compound to be used, i.e., so-called methods of pattern recognition (Varmuza, K. (1983) J. Chem. Info. Comp. Sci. 23, 6) being required. There are several methods of pattern recognition that can be used with some being more suitable than others. The nature of this unique QSAR problem, the appropriate methods to apply, and some of the pitfalls of applying QSAR techniques to predicting toxicity are discussed.

Choroidal malignant melanoma with early vitreous seeding.

Primary choroidal malignant melanoma with extension through the overlying retina is a rarely reported entity, and to our knowledge actual seeding of the vitreous has never been reported. The pathologic findings in a 41-year-old woman who presented with a large amelanotic subretinal mass near the optic disc of the right eye are discussed. Fundus examination preoperatively revealed a concentration of discrete, fleshy, oval to round, vitreous bodies of varying size, limited to the area overlying the mass. Histopathology of this tumor revealed a spindle cell posterior choroidal melanoma with marked atrophy of the overlying retina. At the apex, the retina was discontinuous and melanoma cells extended into the overlying vitreous. Some of the cells surrounded asteroid bodies overlying the tumor, altering their clinical appearance. This behavior, while only involving a small fraction of the tumor cells, may imply a more aggressive tumor.