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PubMed1991

A machine learning approach to computer-aided molecular design.

Preliminary results of a machine learning application concerning computer-aided molecular design applied to drug discovery are presented. The artificial intelligence techniques of machine learning use a sample of active and inactive compounds, which is viewed as a set of positive and negative examples, to allow the induction of a molecular model characterizing the interaction between the compounds and a target molecule. The algorithm is based on a twofold phase. In the first one--the specialization step--the program identifies a number of active/inactive pairs of compounds which appear to be the most useful in order to make the learning process as effective as possible and generates a dictionary of molecular fragments, deemed to be responsible for the activity of the compounds. In the second phase--the generalization step--the fragments thus generated are combined and generalized in order to select the most plausible hypothesis with respect to the sample of compounds. A knowledge base concerning physical and chemical properties is utilized during the inductive process.

Amino Acid Sequence↗
PubMed1996

Determining the size of a total purchasing site to manage the financial risks of rare costly referrals: computer simulation model.

OBJECTIVE: To estimate the financial risks of 15 categories of rare costly referrals for total purchasing sites of different population sizes. DESIGN: Computer simulation of 100 fund years assuming Poisson distribution of referrals. SETTING: British general practices that have opted to become total purchasing sites. Referral rates and price estimates were supplied by South and West Devon Health Commission. MAIN OUTCOME MEASURES: Variation in referral costs to purchasers in relation to size of risk pool (person years at risk). RESULTS: Random variation in referral costs increased as the size of the risk pool decreased. Variation increased greatly below 30,000 person years. The mean simulated cost of the referral categories considered was 2.8% of total NHS hospital and community service costs, and the maximum simulated cost for 7000 person years was 6.8%. Simulated variation was robust to assumption about prices and referral rates for specific types of referral. CONCLUSION: Rare costly referrals seem unlikely to bankrupt total purchasing sites. The management of risk is not in itself justification for total purchasing to be based in several general practices in order to generate large populations. There are other ways of managing risk. Sites can easily explore options by simulations using local referral rates and prices.

Computer Simulation↗
PubMed1990

Formulas predicting the percentile of heart weights by body weight in subjects from birth to 19 years of age.

The values reported by Scholz and his coworkers [Mayo Clin Proc, 63 (1988) 126-136,637] show that distributions of normal heart weights in the period of body growth from birth to 19 years of age are age and sex dependent and actually more dependent on body weight. General formulas are constructed on the basis of the values of Scholz and his coworkers to predict percentile in the population for heart weights by body weight. A mathematical model and a computer program previously published by the author are employed in this study. Analysis of the computer-assisted predicted values and the data on heart weights for specific body weights and percentiles reported by Scholz and his coworkers indicates that the designed computer program for calculating the formula is accurate and reliable. The formulas can determine the mathematical relationship among body weight, heart weight and population percentile. It seems to the author that the computer-assisted predictive formula has limited values in its clinical application since heart weights are to be evaluated practically only in autopsy service in pathology, but that a similar mathematical model as used in this study would be applicable in analysis of other clinical, age- and sex-dependent measurable parameters.

Adult↗
PubMed2001

Designed protein G core variants fold to native-like structures: sequence selection by ORBIT tolerates variation in backbone specification.

The solution structures of two computationally designed core variants of the beta 1 domain of streptococcal protein G (G beta 1) were solved by (1)H NMR methods to assess the robustness of amino acid sequence selection by the ORBIT protein design package under changes in protein backbone specification. One variant has mutations at three of 10 core positions and corresponds to minimal perturbations of the native G beta 1 backbone. The other, with mutations at six of 10 positions, was calculated for a backbone in which the separation between G beta 1's alpha-helix and beta-sheet was increased by 15% relative to native G beta 1. Exchange broadening of some resonances and the complete absence of others in spectra of the sixfold mutant bespeak conformational heterogeneity in this protein. The NMR data were sufficiently abundant, however, to generate structures of similar, moderately high quality for both variants. Both proteins adopt backbone structures similar to their target folds. Moreover, the sequence selection algorithm successfully predicted all core chi(1) angles in both variants, five of six chi(2) angles in the threefold mutant and four of seven chi(2) angles in the sixfold mutant. We conclude that ORBIT calculates sequences that fold specifically to a geometry close to the template, even when the template is moderately perturbed relative to a naturally occurring structure. There are apparently limits to the size of acceptable perturbations: In this study, the larger perturbation led to undesired dynamic behavior.

Bacterial Proteins↗
PubMed2005

Maximizing discovery efficiency with a computationally driven fragment approach.

A reliable and accurate method for the computational design of novel drug candidates has been a passionate pursuit of the pharmaceutical industry. Such technology would dramatically improve the efficiency of drug discovery by quickly and inexpensively providing potent molecules that can be further prioritized for synthesis based on characteristics such as patentability, specific protein-ligand interactions, ease of chemical synthesis, protein selectivity and pharmacological considerations. Described herein is the progress made at Locus Pharmaceuticals Inc toward achieving this ideal with a fragment-driven, computationally directed approach to small-molecule discovery. Specific lead identification examples from Locus Pharmaceuticals discovery programs demonstrate the efficiency and cost-effectiveness realized by such an approach.

Animals↗
PubMed1993

A novel computational tool for automated structure-based drug design.

The computer program LUDI for automated structure-based drug design is described. The program constructs possible new ligands for a given protein of known three-dimensional structure. This novel approach is based upon rules about energetically favourable non-bonded contact geometries between functional groups of the protein and the ligand which are derived from a statistical analysis of crystal packings of organic molecules. In a first step small fragments are docked into the protein binding site in such a way that hydrogen bonds and ionic interactions can be formed with the protein and hydrophobic pockets are filled with lipophilic groups of the ligand. The program can then append further fragments onto a previously positioned fragment or onto an already existing ligand (e.g., a lead structure that one seeks to improve). It is also possible to link several fragments together by bridge fragments to form a complete molecule. All putative ligands retrieved or constructed by LUDI are scored. We use a simple scoring function that was fitted to experimentally determined binding constants of protein-ligand complexes. LUDI is a very fast program with typical execution times of 1-5 min on a work station and is therefore suitable for interactive usage.

Animals↗
PubMed1998

Simple bone cyst: investigation on the presence of gas in the cavity using computed tomography--review of 52 cases.

OBJECTIVE: The purpose of this study was to evaluate whether gas is present in the cavities of simple bone cysts. STUDY DESIGN: Computed tomographic images of 52 simple bone cyst cases were reviewed and compared with the findings at surgery. RESULTS: Whereas gas was confirmed at the time of surgery in 28 cases, no computed tomographic images indicated the presence of gas in the cavity. Bone expansion was noted in 13 of these 28 cases. CONCLUSIONS: From these findings, we concluded that the presence of gas in the simple bone cyst cavity at surgery has been erroneously interpreted.

Adolescent↗
PubMed2000

Stability and bone preservation in custom designed revision hip stems.

Three types of uncemented femoral stems were designed for patients having revision hip surgery, with the goals of promoting axial stability and preserving proximal bone stock. These stems were made individually using computer design and manufacturing technology. Various design features were examined using nonlinear finite element analysis. All stems had lateral, medial, and anterior flares in the proximal region, proximal hydroxyapatite coating, and a collar. Based on a published classification system, the three designs were found suitable for variously encountered cavitary defects. For cases involving small amounts of bone destruction, a primary type of stem was used. With severe cases, an extended polished stem was used. For the worst cases, an extended stem with longitudinal cutting flutes and complete hydroxyapatite coating was necessary. The axial migration was measured radiographically for a 2-year period. The migration rates were comparable with those seen in cemented primary and in custom primary hydroxyapatite coated stems. Dual energy x-ray absorptiometry data were obtained during a 4-year postoperative period. Average bone density in all regions was maintained within 12% of the immediate postoperative values. It was concluded that the proposed system for treating patients needing revision hip surgery showed desirable properties that were comparable to primary hip replacements.

Bone Density↗
PubMedDate not supplied

Electron bolus design for radiotherapy treatment planning: bolus design algorithms.

Computer algorithms to design bolus for electron beam radiotherapy treatment planning were investigated. Because of the significant electron multiple scatter, there is no unique solution to the problem of bolus design. However, using a sequence of operators, a bolus can be designed that attempts to meet three important criteria: adequate dose delivery to the target volume, avoidance of critical structures, and dose homogeneity within the target volume. Initial calculation of bolus shape was based upon creation operators forcing either the physical or the effective depths of the distal surface of the target volume to a specified value. Modification operators were then applied to the bolus to alter the shape to better meet the design criteria. Because the operators each address a single dosimetric issue, they can often adversely affect some other attribute of the dose distribution. In addition, an extension operator is used to design the bolus thickness outside the target volume. Application of these operators is therefore carried out in certain sequences and each may be used more than once in the design of a particular bolus. The effects of these operators on both the bolus and the resulting dose distribution are investigated for test geometries and patient geometries in the nose, parotid, and paraspinal region.

Algorithms↗
PubMed1998

Detection of endotracheal tube obstruction by analysis of the expiratory flow signal.

OBJECTIVE: Acute obstruction of endotracheal tubes (ETT) increases airway pressure, decreases tidal volume, increases the risk of dynamic hyperinflation by prolonging the duration of passive expiration, and prevents reliable calculation of tracheal pressure. We propose a computer-assisted method for detecting ETT obstruction during controlled mechanical ventilation. The method only requires measurement of the expiratory flow. DESIGN: Computer simulation; prospective study in two cases; retrospective study in one case and in seven patients with the adult respiratory distress syndrome (ARDS). SETTING: Laboratory of the Section of Experimental Anaesthesiology (University of Freiburg); surgical adult intensive care units in a university hospital (University of Basel) and in a university affiliated hospital (Zentralklinikum Augsburg). PATIENTS: 3 patients with partial ETT or bronchial obstructions and 7 ARDS patients. MEASUREMENTS AND RESULTS: Expiratory flow was measured using a pneumotachograph and integrated to obtain expiratory volume. The time-constant of passive expiration (tauE) as a function of expired volume [tauE(V(E)) function] was calculated from the expiratory volume/flow curve. We investigated the tauE(V(E)) function of data obtained from: (1) computer simulation of mechanically ventilated homogeneous and inhomogeneous lungs intubated with ETTs of different sizes; (2) one patient with an artificial ETT obstruction of 7.5 and 25% of the cross-sectional area of the ETT (case 1); (3) one patient with ETT obstruction due to secretions (case 2); (4) one patient with acute bronchial constriction (case 3); (5) seven ARDS patients who showed an increase in airway resistance of more than 2 cm H2O x s/l. It was found that an ETT obstruction caused an increase in tauE in early expiration (at high flow), whereas tauE in late expiration was virtually unchanged. The reason for this is the flow dependency of the increase in ETT resistance produced by ETT obstruction. Unlike ETT obstruction, an increase in pure airway resistance produced an increase in tauE throughout expiration. CONCLUSIONS: An ETT obstruction can be reliably distinguished from an increase in pure airway resistance by a characteristic pattern change in the tauE(V(E)) function, which can be detected easily even by an automated pattern recognition system.

Aged↗
PubMed2004

Design of steerable filters for feature detection using canny-like criteria.

We propose a general approach for the design of 2D feature detectors from a class of steerable functions based on the optimization of a Canny-like criterion. In contrast with previous computational designs, our approach is truly 2D and provides filters that have closed-form expressions. It also yields operators that have a better orientation selectivity than the classical gradient or Hessian-based detectors. We illustrate the method with the design of operators for edge and ridge detection. We present some experimental results that demonstrate the performance improvement of these new feature detectors. We propose computationally efficient local optimization algorithms for the estimation of feature orientation. We also introduce the notion of shape-adaptable feature detection and use it for the detection of image corners.

Algorithms↗
PubMed2004

Exploring the chemogenomic knowledge space with annotated chemical libraries.

The recent human genome initiatives have led to the discovery of a multitude of genes that are potentially associated with various pathologic conditions and, thus, have opened new horizons in drug discovery. Simultaneously, annotated chemical libraries have emerged as information-rich databases to integrate biological and chemical data. They can be useful for the discovery of new pharmaceutical leads, the validation of new biotargets and the determination of the structural basis of ligand selectivity within target families. Annotated libraries provide a strong information basis for computational design of target-directed combinatorial libraries, which are a key component of modern drug discovery. Today, the rational design of chemical libraries enhanced with chemogenomics data is a new area of progressive research.

Combinatorial Chemistry Techniques↗
PubMed2006

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated by calmodulin with two bound calciums.

Changes in synaptic strength that underlie memory formation in the CNS are initiated by pulses of Ca2+ flowing through NMDA-type glutamate receptors into postsynaptic spines. Differences in the duration and size of the pulses determine whether a synapse is potentiated or depressed after repetitive synaptic activity. Calmodulin (CaM) is a major Ca2+ effector protein that binds up to four Ca2+ ions. CaM with bound Ca2+ can activate at least six signaling enzymes in the spine. In fluctuating cytosolic Ca2+, a large fraction of free CaM is bound to fewer than four Ca2+ ions. Binding to targets increases the affinity of CaM's remaining Ca2+-binding sites. Thus, initial binding of CaM to a target may depend on the target's affinity for CaM with only one or two bound Ca2+ ions. To study CaM-dependent signaling in the spine, we designed mutant CaMs that bind Ca2+ only at the two N-terminal or two C-terminal sites by using computationally designed mutations to stabilize the inactivated Ca2+-binding domains in the "closed" Ca2+-free conformation. We have measured their interactions with CaMKII, a major Ca2+/CaM target that mediates initiation of long-term potentiation. We show that CaM with two Ca2+ ions bound in its C-terminal lobe not only binds to CaMKII with low micromolar affinity but also partially activates kinase activity. Our results support the idea that competition for binding of CaM with two bound Ca2+ ions may influence significantly the outcome of local Ca2+ signaling in spines and, perhaps, in other signaling pathways.

Calcium↗
PubMed1987

Computer-aided molecular design.

Theoretical chemistry, as implemented on fast computers, is beginning to yield accurate predictions of the thermodynamic and kinetic properties of large molecular assemblies. In addition to providing detailed insights into the origins of molecular activity, theoretical calculations can be used to design new molecules with specific properties. This article describes two types of calculations that show special promise as design tools, the thermodynamic cycle-perturbation method and the Brownian reactive dynamics method. These methods can be applied to calculate equilibrium and rate constants that describe many aspects of molecular recognition, stability, and reactivity.

Chemistry↗
PubMed1984

Vascular surgical data registries for small computers.

Recent designs for computer-based vascular surgical registries and clinical data bases have employed large centralized systems with formal programming and mass storage. Small computers, of the types created for office use or for word processing, now contain sufficient speed and memory storage capacity to allow construction of decentralized office-based registries. Using a standardized dictionary of terms and a method of data organization adapted to word processing, we have created a new vascular surgery data registry, "VASREG." Data files are organized without programming, and a limited number of powerful logical statements in English are used for sorting. The capacity is 25,000 records with current inexpensive memory technology. VASREG is adaptable to computers made by a variety of manufacturers, and interface programs are available for conversion of the word processor formated registry data into forms suitable for analysis by programs written in a standard programming language. This is a low-cost clinical data registry available to any physician. With a standardized dictionary, preparation of regional and national statistical summaries may be facilitated.

Computers↗
PubMed1977

The use of photogrammetry in tissue compensator design. Part II: experimental verification of compensator design.

A computer algorithm for designing sheet lead tissue compensators is described. Corrections are made for scatter within the radiation field as well as the shape of the patient for the mantle fields used in treating Hodgkin's disease. The method was tested experimentally with a phantom and found to be clinically acceptable. The advantages of employing this technique with parallel opposed fields are emphasized.

Hodgkin Disease↗
PubMed1995

Abdominal computed tomographic scan in the selection of patients with mucinous peritoneal carcinomatosis for cytoreductive surgery.

BACKGROUND: Cytoreductive surgery and intraperitoneal chemotherapy have been used to treat peritoneal carcinomatosis. A complete surgical resection is required for optimal results to be achieved. This study evaluated the preoperative computed tomographic (CT) findings in patients with mucinous peritoneal carcinomatosis in order to predict the probability of a complete resection. STUDY DESIGN: Computed tomographic scans of the abdomen and pelvis were reviewed retrospectively in 45 patients with a diagnosis of mucinous peritoneal carcinomatosis who were treated with surgery and intraperitoneal chemotherapy. According to the completeness of cytoreduction, patients were divided into two groups. Patients in the first group (n = 25) had complete cytoreduction (CR) with no tumor deposits 2.5 mm in diameter or larger left behind. The surgical resection of tumor was incomplete in the second group of patients (n = 20). Sixteen CT parameters were initially examined in each group of patients and statistically evaluated according to the completeness of the cytoreductive surgical procedure. RESULTS: The incidences of six CT findings were significantly different in the two groups of patients. These findings were: tumor volume in small bowel mesentery (p < 0.001), tumor volume in proximal jejunum (p = 0.003), tumor volume in distal jejunum (p = 0.002), tumor volume in proximal ileum (p = 0.003), mesentery configuration (p < 0.001), and obstruction of bowel segments by tumor (p < 0.001). A statistical approach using a tree-structured diagram showed that patients with both obstruction of bowel segments by tumor and tumor diameter greater than 0.5 cm on small bowel surfaces exclusive of distal ileum on preoperative CT scan, had an 88 percent probability of incomplete resection. Patients without these two CT findings had a 92 percent probability of complete resection. CONCLUSIONS: This study shows that selection criteria for patients with mucinous peritoneal carcinomatosis are available on a preoperative CT scan of the abdomen and pelvis. Patients whose scans show obstruction of bowel segments by tumor and tumor diameter greater than 0.5 cm on small bowel surfaces exclusive of distal ileum are unlikely to be candidates for cytoreductive surgery for the treatment of peritoneal carcinomatosis.

Adenocarcinoma, Mucinous↗