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At least 1,135 records · Page 63Linked to original sources
PubMed2000

Rational design of cyclodextrin glycosyltransferase from Bacillus circulans strain 251 to increase alpha-cyclodextrin production.

Cyclodextrin glycosyltransferases (CGTase) (EC 2.4.1.19) are extracellular bacterial enzymes that generate cyclodextrins from starch. All known CGTases produce mixtures of alpha, beta, and gamma-cyclodextrins. A maltononaose inhibitor bound to the active site of the CGTase from Bacillus circulans strain 251 revealed sugar binding subsites, distant from the catalytic residues, which have been proposed to be involved in the cyclodextrin size specificity of these enzymes. To probe the importance of these distant substrate binding subsites for the alpha, beta, and gamma-cyclodextrin product ratios of the various CGTases, we have constructed three single and one double mutant, Y89G, Y89D, S146P and Y89D/S146P, using site-directed mutagenesis. The mutations affected the cyclization, coupling; disproportionation and hydrolyzing reactions of the enzyme. The double mutant Y89D/S146P showed a twofold increase in the production of alpha-cyclodextrin from starch. This mutant protein was crystallized and its X-ray structure, in a complex with a maltohexaose inhibitor, was determined at 2.4 A resolution. The bound maltohexaose molecule displayed a binding different from the maltononaose inhibitor, allowing rationalization of the observed change in product specificity. Hydrogen bonds (S146) and hydrophobic contacts (Y89) appear to contribute strongly to the size of cyclodextrin products formed and thus to CGTase product specificity. Changes in sugar binding subsites -3 and -7 thus result in mutant proteins with changed cyclodextrin production specificity.

Amino Acid Substitution↗
PubMed1998

Prognostic factors and rational approach in the treatment of submucosal cancer of the stomach.

In early gastric cancer, lymph node metastasis is known to be a prognostic factor. A retrospective study of 134 patients with submucosal gastric cancer (SMGC) who had undergone gastrectomy with lymph node dissection was performed to evaluate the prognostic factors and indication of postoperative chemotherapy. Five-year disease-free survival rate for 121 patients without nodal metastasis was 100% with (n = 62) or without postoperative chemotherapy (n = 59). On the other hand, it was 72.9% for 13 patients with nodal metastases, although all patients had undergone D2 or D3 resection and received postoperative chemotherapy. Tumor recurrence occurred only in three patients (n = 3) with alpha-fetoprotein (AFP) producing cancer and lymph node metastasis. Multivariate analysis with the Cox's proportional hazard model revealed AFP positivity to be a new independent prognostic factor in addition to lymph node metastasis in the patients with SMGC. Our findings suggest that routine use of postoperative chemotherapy does not appear rational for the patients without nodal metastasis and that new modalities of operation and chemotherapy may be necessary for the patients with AFP producing SMGC with nodal metastasis. The necessity of chemotherapy in conventional-type SMGCs with nodal involvement remains to be studied in future.

Adenocarcinoma↗
PubMed1994

A rational approach to risk assessment requires the use of biological information: an analysis of the National Toxicology Program (NTP), final report of the advisory review by the NTP Board of Scientific Counselors.

The National Toxicology Program (NTP) Board of Scientific Counselors met on April 14 and 15, 1992 to review the NTP. This paper provides an overview of the Board's Report with an emphasis on the recommendations made by the Carcinogenesis Working Group. The prime overall recommendation is that the NTP should move from a focus on hazard identification to an emphasis on providing the type of biological information that needs to be incorporated into the risk assessment process. This would involve a hypothesis-driven mechanism of action approach aimed at understanding the basis for the actions of the chemicals of interest. Relevant examples are provided. Scientists from the National Institute of Environmental Health Sciences' (NIEHS) intramural program and those outside of NIEHS should be included in the research effort. This strategy would permit a more rational approach toward both test development and design (e.g., selection of the high dose to be employed), and the interpretation of test results (e.g., addressing questions pertaining to dose-response relationships and species to species extrapolation). The overall goal would be to provide a reasonable assessment of the possible hazard that a chemical might pose to people in light of realistic conditions of exposure.

Animals↗
PubMed1995

Site-directed mutagenesis--molecular biology and rational drug design.

Using site-directed mutagenesis, we have determined the location and composition of the binding sites in human IL-1 alpha and IL-1 beta for the Type I IL-1 receptor (IL-1R). The binding site in each ligand is a discontinuous epitope made up of at least seven amino acids whose side chains are exposed on a contiguous region of the protein surface. Although human IL-1 alpha and IL-1 beta have similar affinities and cross-compete for binding to the human Type I IL-1R, the binding site residues are not identical in the two ligands. In addition, the residues in the binding site of each ligand contribute differently to binding of the human versus the mouse IL-1R. The structure of the IL-1 binding site has implications for the rational design of IL-1 antagonists.

Animals↗
PubMed1994

GREEN: a program package for docking studies in rational drug design.

A program package, GREEN, has been developed that enables docking studies between ligand molecules and a protein molecule. Based on the structure of the protein molecule, the physical and chemical environment of the ligand-binding site is expressed as three-dimensional grid-point data. The grid-point data are used for the real-time evaluation of the protein-ligand interaction energy, as well as for the graphical representation of the binding-site environment. The interactive docking operation is facilitated by various built-in functions, such as energy minimization, energy contribution analysis and logging of the manipulation trajectory. Interactive modeling functions are incorporated for designing new ligand molecules while considering the binding-site environment and the protein-ligand interaction. As an example of the application of GREEN, a docking study is presented on the complex between trypsin and a synthetic trypsin inhibitor. The program package will be useful for rational drug design, based on the 3D structure of the target protein.

Algorithms↗
PubMed1994

Rational design of novel neurotensin mimetics: discovery of a pharmacologically unprecedented agent exhibiting concentration-dependent dual effects as antagonist and full agonist.

We report the rational design of novel neurotensin mimetics through use of the Multiple Template Approach. This approach is based on our notion that a flexible peptide can be replaced by a partially flexible molecule, identified through testing a comparatively small number of molecules possessing a different intrinsic availability of conformations of the native peptide. The Multiple Template Approach has culminated in the discovery of a pharmacologically unprecedented agent, which behaves as a neurotensin antagonist at low concentration and as a full neurotensin agonist at high concentration.

Amino Acid Sequence↗
PubMed1996

Identifying Patient Risk: The Basis for Rational Discharge Planning After Acute Myocardial Infarction.

Variations in the management of patients with chest pain and acute myocardial infarction (MI) can significantly affect hospital length of stay and cost. Risk stratification of such patients, combined with data about effective therapies, provides the basis for developing rational guidelines for patient care that can improve efficiency while maintaining quality of care. Such standardized management approaches are often referred to as pathways or CareMaps. To be most effective in guiding hospital course and early discharge planning, risk stratification strategies must be applied early in a patient's course with continuous updating. The process of identifying risk in a patient with acute chest pain occurs in two segments: assessing the risk of acute MI at presentation, and subsequently assessing the morbidity and mortality risk of patients diagnosed with acute MI. Identification of patient risk at presentation has been the object of intense investigation. The history, physical exam, initial electrocardiogram, and cardiac enzymes are the mainstays of the process, but because of inherent weaknesses in this approach (>25% of acute MIs missed initial screening), several risk stratification models have been developed. To date these models have not been widely employed, however. Very sensitive early cardiac markers, such as troponin T, and the use of diagnostic echocardiography or cardiolite perfusion imaging during pain are also being investigated. Chest pain observation units are an alternate strategy and have obviated the need to admit many low- to moderate-risk chest pain patients. In these protocol-driven units, continuous physiologic monitoring and serial cardiac enzymes and electrocardiography over a 9-12 hour period refine the risk assessment. For the majority who "rule out," the risk of subsequent MI or death is very low. Cost savings due to reduced length of stay and more efficient resource utilization are 63-76% compared with conventional word or cardiac care unit management. For patients with acute MI, baseline characteristics, complications, and laboratory and diagnostic testing help define the risk of morbidity and mortality and guide management through the immediate post-MI phase and long term. Many models incorporating these features have been proposed for risk stratification after acute MI, and they have implications for both timing of discharge and necessary diagnostic testing. Savings by employing risk stratification to guide hospital course and discharge planning could be 30-44% in some patient groups. In conclusion, risk stratification models can facilitate early discharge planning, potentially reducing hospital stay, improving resource utilization, and reducing costs.

Journal Article↗
PubMed1992

Acidic phosphoproteins from bone matrix: a structural rationalization of their role in biomineralization.

Osteopontin, bone sialoprotein, and bone acidic glycoprotein-75 are three acidic phosphoproteins that are isolated from the mineralized phase of bone matrix, are synthesized by osteoblastic cells, and are generally restricted in their distribution to calcified tissues. Although each is a distinct gene product, these proteins share aspartic/glutamic acid contents of 30-36% and each contains multiple phosphoryl and sialyl groups. These properties, plus a strict relationship of acidic macromolecules with cell-controlled mineralization throughout nature, suggest functions in calcium binding and nucleation of calcium hydroxyapatite crystal formation. However, direct proof for such roles is still largely indirect in nature. The purpose of this review is to present two speculative hypotheses regarding acidic phosphoprotein function. The goal was to use new sequence information along with database comparisons to develop a structural rationalization of how these proteins may function in calcium handling by bone. For example, our analysis has identified a conserved polyacidic stretch in all three phosphoproteins which we propose mediates metal binding. Also, conserved motifs were identified that are analogous with those for casein kinase II phosphorylation sites and whose number correlates well with that of phosphoryl groups/protein. A two-state conformational model of calcium binding by bone matrix acidic phosphoproteins is described which incorporates these findings.

Amino Acid Sequence↗
PubMed1992

Structural biology and diabetes mellitus: molecular pathogenesis and rational drug design.

Emerging concepts in the aetiology and pathogenesis of Type 1 (insulin-dependent) diabetes mellitus may offer new opportunities for treatment and cure. Here we describe recent advances in structural molecular biology and molecular design relevant to rational drug discovery. Such approaches focus on the three-dimensional structures of macromolecules and their interactions. In the coming decade such techniques may be applied to a wide variety of diabetes-related targets.

Amino Acid Sequence↗
PubMed1993

Delta-toxin, unlike melittin, has only hemolytic activity and no antimicrobial activity: rationalization of this specific biological activity.

The antimicrobial activity of a synthetic peptide corresponding to delta-hemolysin had been examined. The peptide did not exhibit antimicrobial activity against gram negative and gram positive micro-organisms unlike other hemolytic peptides like melittin. This lack of antibacterial activity arises due to the inability of delta-hemolysin to perturb the negatively charged bacterial cell surface and permeabilize the bacterial plasma membrane. However, the red blood cell surface has a structure considerably different from bacteria and does not act as a barrier to molecules reaching the lipid membrane. Hence delta-toxin can lyse erythrocytes. Thus, the specificity in biological activity has been rationalized in terms of differences in the interaction of the toxin with the bacterial and red blood cell surfaces.

Amino Acid Sequence↗
PubMed1978

Screening for hypertension: a rational approach.

A strategy for the control of hypertension in communities is presented as a staged program. Stage I consists of the evaluation and improvement of hypertension management in health care facilities. Stage II entails case-finding in health care facilities. Finally, Stage III involves targeted screening in the community. While isolated screening programs have been justly labeled "irrational", such a sequential strategy represents a highly rational approach to the community control of hypertension.

Community Health Services↗
PubMed1997

Evaluating the rational extent of dissection in radical esophagectomy for invasive carcinoma of the thoracic esophagus.

To define the rational extent of dissection in radical esophagectomy for esophageal cancer, survival was studied according to nodal status in 154 patients undergoing extended radical esophagectomy. The incidence of cervical metastasis in patients with upper or middle esophageal tumors did not differ between those with favorable (grade N < or = 4) or unfavorable (grade N > or = 5) lymph node status, at 28.6% vs 20%, respectively. On the other hand, in patients with lower esophageal tumors, the incidence of cervical metastasis was significantly lower in those with favorable grade (grade N < or = 4) node status than in those with unfavorable grade (grade N > or = 5) node status, at 6.5% vs 46.7%, respectively. Survival did not differ in patients with upper or middle esophageal tumors according to whether they had regional (n = 42) or distant (n = 15) lymph node metastases, the 5-year survival rates being 11.6% vs 25%, respectively. However, in patients with lower esophageal tumors, none of 10 patients with distant node metastases survived for more than 4 years, whereas the survival rate was 43.7% at 5 years for 36 patients with regional node metastases. These results show that cervical lymphadenectomy should only be performed as part of radical esophagectomy in those patients with upper or middle esophageal cancer.

Adult↗
PubMed1989

The rationalization of liposuction: toward a safer and more accurate technique.

Liposuction, like all surgical procedures, is subject to complications and unfavorable results. Since it is a closed procedure and departs from the usual concept of surgery, its practice is, to a large extent, based on subjective intraoperative estimation. Therefore, it is liable to errors that might have serious local and systemic consequences. In an attempt to improve the technique, the authors have designed new instruments: the "tunnel tracer" and the "guided cannulae." They provide the basis for systematizing the procedure and applying it in a more rational manner. With these instruments and the methodology described in this article, over the last three years we have obtained very satisfactory results and notable reduced morbidity. The advantages are less trauma, less risk, less hemorrhage, less effort for the surgeon, and greater precision.

Equipment Design↗
PubMedDate not supplied

Tumor spread in superficial esophageal cancer: histopathologic basis for rational surgical treatment.

To formulate a rational approach for the surgical treatment of patients with superficial esophageal cancer (SEC), tumor spread was clinicopathologically studied in 89 patients with SEC. There were 31 mucosal and 58 submucosal tumors. Lymph node metastases were not found in any of those with a mucosal tumor, while one or more lymph nodes were positive for cancer in 41.4% of those with a submucosal tumor. Furthermore, cancer metastasized to extramediastinal nodes, including cervical and abdominal nodes, in 14 patients, accounting for 58.3% of those with nodal metastasis. The 5-year survival rate was 100% and there were no recurrences after esophagectomy in those with a mucosal tumor, whereas the survival rate of those with a submucosal tumor was 64.3% at 5 years (p < 0.01). Based on the different biological behavior of mucosal and submucosal esophageal cancer, we conclude that mucosal tumors may be adequately treated by any type of local resection but submucosal tumors require a subtotal esophagectomy with systematic lymphadenectomy involving the cervical, mediastinal, and abdominal nodes for cure.

Adult↗
PubMed1996

Rationally designed non-peptides: variously substituted piperazine libraries for the discovery of bradykinin antagonists and other G-protein-coupled receptor ligands.

Molecular modeling studies of potent decapeptide bradykinin antagonists suggested the de novo design of peptide mimetics based on a 1,2,3,4-tetrasubstituted 1,4-piperazin-6-one scaffold. These de novo-designed antagonists exhibited only modest potency (IC50 approximately 55 microM) on a cloned human B2 receptor and antagonist activity in an in vitro human-cell functional assay. The success of these structures led to the creation of prototype libraries based on variously substituted 1,4-piperazine scaffolds, which allowed a rapid and general search of pharmacophores attached to a piperazine scaffold. The parent piperazinedione structures and fully reduced piperazine libraries differ from recently reported diketopiperazine libraries in the use of diverse nonnatural amino acids, on-resin-submonomer synthesis to provide more diverse N-substituted structures, and the adaptation of simultaneous ring closure and resin cleavage to drive the formation of highly hindered amide bonds. Using this chemistry, a rationally directed non-peptide library of approximately 2500 N,N'-disubstituted piperazines and piperazinediones was synthesized and screened for ligand affinity on bradykinin, neurokinin, and opioid receptors. A number of lead structures were identified. Notably, a bradykinin antagonist lead, CP-2458, with good receptor selectivity and antagonist activity in human-cell assays was identified and is undergoing optimization by traditional and combinatorial methods.

Acetylation↗
PubMed1985

Rationalization of some genetic anticodonic assignments.

The genetic code appears to be a logic matrix in which, generally speaking, there is a correlation between the hydrophobicities of amino acids and their anticodonic nucleotides. There are several exceptions to this generality, however, and using previous data on hydrophobicity and binding constants, coupled with new data on reaction rates, we rationalize several of the anticodonic assignments.

Amino Acids↗
PubMed1976

Apparent pharmacokinetics of PCB components in growing pigs and lambs when fed a ration containing Aroclor 1254.

Young growing lambs and pigs were fed a ration containing 200 ppm of Aroclor 1254 for 35 days and then switched to "clean" feed. Blood and fat samples were collected periodically throughout the experiment and analyzed for components of Aroclor 1254 and total PCB. Several components are apparently accumulated and eliminated at different rates within each species, as seen by comparing gas chromatograph tracings, accumulation ratios and apparent rate constants of elimination. Differences in accumulation and elimination of Aroclor components, some of which were apparently caused by differences in growth rates, were also seen between pigs and lambs. Variable growth rates of different species of food producing animals are an important factor to consider when dealing with tissue distribution and residues of polychlorinated biphenyls for determination of carcass disposition, as well as accumulation of toxic concentrations in the animal body.

Adipose Tissue↗
PubMed1995

Risk assessment of adverse pulmonary effects induced by adrenaline beta-receptor antagonists and rational drug dosage regimen based on receptor occupancy.

To clarify the beta-1 selectivity of beta-adrenergic receptor blocking agents (beta-blocking agents) after typical oral doses, the relationships between the effects on exercise heart rate or FEV1 and beta-1 or beta-2 receptor occupancies (phi 1, phi 2) of seven beta-blocking agents, acebutolol, atenolol, metoprolol, oxprenolol, timolol, propranolol, and pindolol were analyzed retrospectively. Nonlinear relationships between the pharmacologic effect and phi 1 and between the pulmonary adverse effect and phi 2 were obtained. Based on these findings, a new index of cardiovascular selectivity is proposed, given by the ratio of beta-1 receptor occupancy to beta-2 receptor occupancy (phi 1/phi 2). Using this new index, there was a little difference in beta-1 selectivity between acebutolol and pindolol (3.1:1.0), in contrast to a marked difference in beta-1 selectivity (320:1) as a conventional index between these two drugs. This finding indicates that even beta-1 selective drugs must be administered carefully to patients with pulmonary disease. Furthermore, the relationship between the pharmacologic or pulmonary effects and phi 1 or phi 2 has been analyzed quantitatively with a ternary complex model and used to develop rational dosage regimens for beta-1 selective beta-blocking agents, such as atenolol, to obtain the desired pharmacologic effects with minimum adverse pulmonary effects.

Adrenergic beta-Antagonists↗