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At least 397 records · Page 22Linked to original sources
PubMedDate not supplied

Screening for new antidepressant leads of multiple activities by support vector machines.

Virtual screening was carried out against 21 biological targets related to depression by support vector machine classification using the same atom-type descriptors. The models were effective as 0.2-0.8 of theoretical enrichments of the external test data sets could be achieved, depending on the target. The set of predicted active molecules had large diversity and contained examples with high dissimilarity to the compounds of training sets. Filtering the database of known antidepressants by all 21 models it was found that on average compounds were classified active for 2.3 targets.

Antidepressive Agents↗
PubMed2004

Influences on participation in a community-based colorectal neoplasia screening program by virtual colonoscopy in Australia.

OBJECTIVE: To determine the effect of certain personal and health behaviour characteristics on participation in a community-based colorectal neoplasia (CRN) screening program using virtual colonoscopy. METHODS: The study population comprised randomly selected subjects from the State electoral roll; screening by virtual colonoscopy was offered through letter of invitation. For non-responders, a further invitation was sent a month later. Non-response after a further month led to subjects being considered non-participants. Non-participants were contacted by letter to complete a structured questionnaire; participants completed a similar questionnaire immediately after their screening virtual colonoscopy. RESULTS: Discussing the invitation to screening with someone else increased the likelihood of participation by 63% (prevalence ratio 1.63, 95% CI 1.38-1.93); knowing someone with cancer increased the likelihood of participation by 23% (PR 1.23, 95% CI 1.07-1.42). Among participants who discussed screening with another individual, the spouse was the most common (71%). Subjects who were single were less likely to participate (PR 0.79, 95% CI 0.67-0.94). The strongest reported influence for participation was information provided in the letter of invitation (29.8%). The most common reasons for non-participation were lack of time and perceived good health. CONCLUSIONS AND IMPLICATIONS: This study suggests that a simple strategy to facilitate participation is to encourage subjects to discuss screening with others; further, to recognise that this may be most difficult for those who are single. Information provided to subjects prior to screening positively contributes to participation.

Colonoscopy↗
PubMed2005

Virtual colonoscopy for primary screening. The future is now.

Virtual colonoscopy (VC) is a minimally invasive tool that utilizes modern CT technology for colorectal evaluation. Since its inception in 1994, VC has continued to rapidly evolve and improve as a diagnostic screening tool. Early success using primary two-dimensional (2D) detection in polyp-rich cohorts was followed by disappointing results in low prevalence populations. Subsequent introduction of the three-dimensional (3D) endoluminal display for primary polyp detection and oral contrast tagging has transformed VC into an effective primary screening tool. This state-of-the-art VC technique has already proven to be a viable enterprise when combined with existing optical colonoscopy practice. More widespread implementation of VC screening faces multiple challenges, but these are all greatly overshadowed by the immediate need for increased participation in effective colorectal screening. Given its relatively noninvasive nature and the wide availability of CT, VC holds significant potential for addressing a very important yet preventable public health concern. This review will cover current VC technique, compare the existing multi-center VC trials, discuss issues related to primary VC screening, and briefly update the progress of our VC screening program.

Algorithms↗
PubMed2003

Conformational analysis by intersection: CONAN.

As high throughput techniques in chemical synthesis and screening improve, more demands are placed on computer assisted design and virtual screening. Many of these computational methods require one or more three-dimensional conformations for molecules, creating a demand for a conformational analysis tool that can rapidly and robustly cover the low-energy conformational spaces of small molecules. A new algorithm of intersection is presented here, which quickly generates (on average <0.5 seconds/stereoisomer) a complete description of the low energy conformational space of a small molecule. The molecule is first decomposed into nonoverlapping nodes N (usually rings) and overlapping paths P with conformations (N and P) generated in an offline process. In a second step the node and path data are combined to form distinct conformers of the molecule. Finally, heuristics are applied after intersection to generate a small representative collection of conformations that span the conformational space. In a study of approximately 97,000 randomly selected molecules from the MDDR, results are presented that explore these conformations and their ability to cover low-energy conformational space.

Journal Article↗
PubMedDate not supplied

Designing targeted libraries with genetic algorithms.

In combinatorial synthesis, molecules are assembled by linking chemically similar fragments. Because the number of available chemical fragments often greatly exceeds the number that can be used in one synthetic experiment, one needs a rational method for choosing a subset of desirable fragments. If a combinatorial library is to be targeted against a particular biological activity, virtual screening methods can be used to predict which molecules in a virtual library are most likely to be active. When the number of possible molecules in a virtual library is very large, genetic algorithms (GAs) or simulated annealing can be used to quickly find high-scoring molecules by sampling a small subset of the total combinatorial space. We previously demonstrated how a GA can be used to select a subset of fragments for a combinatorial library, and we used topology-based methods of scoring. Here we extend that earlier work in three ways. (1) We demonstrate use of the GA with 3D scoring methods developed in our laboratory. (2) We show that the approach of assembling libraries from fragments in high-scoring molecules is a reasonable one. (3) We compare results from a library-based GA to those from a molecule-based GA.

Algorithms↗
PubMed2003

Partitioning methods for the identification of active molecules.

The dramatically increasing number of compounds that become available for biological evaluation presents a significant challenge for database design, management, and mining. Computational approaches for screening, profiling, or filtering of large compound collections are by now widely used in pharmaceutical research. Among popular compound classification and database mining techniques, partitioning methods are computationally very efficient and particularly suitable for the analysis of increasingly large molecular databases, as they do not depend on pair-wise comparisons of compounds to assess molecular similarity or diversity. Promising applications of partitioning algorithms include diversity selection, searching for compounds with desired biological activity, or the derivation of predictive models from screening datasets. Compound partitioning is introduced here in the context of virtual screening and different partitioning methods are discussed that operate in low-dimensional or other chemical descriptor spaces, including a number of practical drug-discovery-related applications.

Algorithms↗
PubMed2006

Orphan nuclear receptors, excellent targets of drug discovery.

To date, the pharmaceutical industry has placed a considerable amount of interest in the discovery of drug targets and diagnostics. One of the most challenging areas of drug discovery today is the search for novel receptor-ligand pairs. Nuclear receptors comprise a large superfamily of ligand-dependent transcription factors that regulate the expression of genes critical for a variety of biological processes, including development, growth, differentiation, and homeostasis. Orphan nuclear receptors, for which the ligands are not yet identified, represent the most ancient component of the nuclear receptor superfamily. Orphan nuclear receptors not only offer a unique system to uncover novel signaling pathways that impact human health, but also provide excellent targets of drug discoveries for a variety of human diseases. This review highlights advances made on ligand identification for orphan nuclear receptors using transgenic mouse models, cell-based screening, direct binding, structure-based assays, and computer-aided virtual screening. With rapid advances in combinatorial chemistry and high throughput screening, along with other modern technologies, this field promises a bountiful harvest.

Animals↗
PubMed2006

Investigation of the binding mode of (-)-meptazinol and bis-meptazinol derivatives on acetylcholinesterase using a molecular docking method.

Molecular docking has been performed to investigate the binding mode of (-)-meptazinol (MEP) with acetylcholinesterase (AChE) and to screen bis-meptazinol (bis-MEP) derivatives for preferable synthetic candidates virtually. A reliable and practical docking method for investigation of AChE ligands was established by the comparison of two widely used docking programs, FlexX and GOLD. In our hands, we had more luck using GOLD than FlexX in reproducing the experimental poses of known ligands (RMSD<1.5 A). GOLD fitness values of known ligands were also in good agreement with their activities. In the present GOLD docking protocol, (-)-MEP seemed to bind with the enzyme catalytic site in an open-gate conformation through strong hydrophobic interactions and a hydrogen bond. Virtual screening of a potential candidate compound library suggested that the most promising 15 bis-MEP derivatives on the list were mainly derived from (-)-MEP with conformations of (S,S) and (SR,RS) and with a 2- to 7-carbon linkage. Although there are still no biological results to confirm the predictive power of this method, the current study could provide an alternate tool for structural optimization of (-)-MEP as new AChE inhibitors. [Figure: see text].

Acetylcholinesterase↗
PubMed2005

Human responses to augmented virtual scaffolding models.

This study investigated the effect of adding real planks, in virtual scaffolding models of elevation, on human performance in a surround-screen virtual reality (SSVR) system. Twenty-four construction workers and 24 inexperienced controls performed walking tasks on real and virtual planks at three virtual heights (0, 6 m, 12 m) and two scaffolding-platform-width conditions (30, 60 cm). Gait patterns, walking instability measurements and cardiovascular reactivity were assessed. The results showed differences in human responses to real vs. virtual planks in walking patterns, instability score and heart-rate inter-beat intervals; it appeared that adding real planks in the SSVR virtual scaffolding model enhanced the quality of SSVR as a human - environment interface research tool. In addition, there were significant differences in performance between construction workers and the control group. The inexperienced participants were more unstable as compared to construction workers. Both groups increased their stride length with repetitions of the task, indicating a possibly confidence- or habit-related learning effect. The practical implications of this study are in the adoption of augmented virtual models of elevated construction environments for injury prevention research, and the development of programme for balance-control training to reduce the risk of falls at elevation before workers enter a construction job.

Adult↗
PubMed2002

Optimization of focused chemical libraries using recursive partitioning.

A number of methods currently exist for designing chemical libraries. General or universal libraries use a measurement of chemical diversity in their design and seek to cover as much of chemical space as possible in order to maximize the likelihood of discovering a novel lead class of active compounds. Focused chemical libraries are then synthesized to expand on this particular class and thoroughly explore the space about it. Rarely, however, is relevant biological data tightly incorporated in the design of focused libraries. Recursive partitioning is a statistical technique that is used to quickly build SAR models from high-throughput screening data sets and associated chemical descriptors. Using these models in a virtual screening mode significantly increases the probability of finding other active compounds. The predicted activity can be also be used as the fitness function for a genetic algorithm that is designed to select monomer subsets having a higher probability of being active. This dramatically reduces the number of compounds that need to be synthesized in focused libraries thus saving considerable time, effort and expense. This paper describes how recursive partitioning models are used to optimize the design of focused chemical libraries.

Chemistry, Pharmaceutical↗
PubMed2006

eHiTS: a new fast, exhaustive flexible ligand docking system.

The flexible ligand docking problem is divided into two subproblems: pose/conformation search and scoring function. For successful virtual screening the search algorithm must be fast and able to find the optimal binding pose and conformation of the ligand. Statistical analysis of experimental data of bound ligand conformations is presented with conclusions about the sampling requirements for docking algorithms. eHiTS is an exhaustive flexible-docking method that systematically covers the part of the conformational and positional search space that avoids severe steric clashes, producing highly accurate docking poses at a speed practical for virtual high-throughput screening. The customizable scoring function of eHiTS combines novel terms (based on local surface point contact evaluation) with traditional empirical and statistical approaches. Validation results of eHiTS are presented and compared to three other docking software on a set of 91 PDB structures that are common to the validation sets published for the other programs.

Algorithms↗
PubMed2004

Custom chemical microarray production and affinity fingerprinting for the S1 pocket of factor VIIa.

The goal of this study was to explore the applicability of surface plasmon resonance (SPR)-based fragment screening to identify compounds that bind to factor VIIa (FVIIa). Based on pharmacophore models virtual screening approaches, we selected fragments anticipated to have a reasonable chance of binding to the S1-binding pocket of FVIIa and immobilized these compounds on microarrays. In affinity fingerprinting experiments, a number of compounds were identified to be specifically interacting with FVIIa and shown to fall into four structural classes. The results demonstrate that the chemical microarray technology platform using SPR detection generates unique chemobiological information that is useful for de novo discovery and lead development and allows the detection of weak interactions with ligands of low molecular weight.

Chemistry, Pharmaceutical↗
PubMed2005

The discovery of novel chemotypes of p38 kinase inhibitors.

In the late 1970s and the early 1980s the initial p38 chemotype, the triaryl imidazoles, was discovered as an off-target effect during the development of cyclooxygenase and 5-lipoxygenase inhibitors long before the identity of the p38 kinase was known. During the last 10 years a number of novel p38 chemotypes were discovered via high throughput screening. More recently, the first series of p38 inhibitors discovered by xray crystallographic and virtual screening was announced. Finally, throughout the life span of p38 drug discovery programs significant medicinal chemistry effort has continually been placed on the design of new inhibitors from known chemotypes using molecular modeling, protein crystallography, hybrid design and simply sound intuition. Indeed, the search for p38 kinase inhibitors offers an excellent historical perspective as to how technological changes that have taken place in the pharmaceutical industry over the last decade, have affected the ways in which new leads are discovered and advanced. It is the intent of this review to highlight the discoveries of novel p38 chemotypes, emphasizing where possible the key technologies used in the discoveries and the knowledge gained from each discovery.

Anti-Inflammatory Agents↗
PubMed2003

Experimental studies of virtual reality-delivered compared to conventional exercise programs for rehabilitation.

This paper presents preliminary data from two clinical trials currently underway using flat screen virtual reality (VR) technology for physical rehabilitation. In the first study, we are comparing a VR-delivered exercise program to a conventional exercise program for the rehabilitation of shoulder joint range-of-motion in patients with chronic frozen shoulder. In the second study, we are comparing two exercise programs, VR and conventional, for balance retraining in subjects post-traumatic brain injury. Effective VR-based rehabilitation that is easily adapted for individuals to use both in inpatient, outpatient and home-based care could be used as a supplement or alternative to conventional therapy. If this new treatment approach is found to be effective, it could provide a way to encourage exercise and treatment compliance, provide safe and motivating therapy and could lead to the ability to provide exercises to clients in distant locations through telehealth applications of VR treatment. VR is a new technology and the possibilities for rehabilitation are only just beginning to be assessed.

Brain Injuries↗
PubMed2006

Progressive docking: a hybrid QSAR/docking approach for accelerating in silico high throughput screening.

A combination of protein-ligand docking and ligand-based QSAR approaches has been elaborated, aiming to speed-up the process of virtual screening. In particular, this approach utilizes docking scores generated for already processed compounds to build predictive QSAR models that, in turn, assess hypothetical target binding affinities for yet undocked entries. The "progressive docking" has been tested on drug-like substances from the NCI database that have been docked into several unrelated targets, including human sex hormone binding globulin (SHBG), carbonic anhydrase, corticosteroid-binding globulin, SARS 3C-like protease, and HIV1 reverse transcriptase. We demonstrate that progressive docking can reduce the amount of computations 1.2- to 2.6-fold (when compared to traditional docking), while maintaining 80-99% hit recovery rates. This progressive-docking procedure, therefore, substantially accelerates high throughput screening, especially when using high accuracy (slower) docking approaches and large-sized datasets, and has allowed us to identify several novel potent nonsteroidal SHBG ligands.

Binding Sites↗
PubMed2002

Applications of SHAPES screening in drug discovery.

The SHAPES strategy combines nuclear magnetic resonance (NMR) screening of a library of small drug-like molecules with a variety of complementary methods, such as virtual screening, high throughput enzymatic assays, combinatorial chemistry, X-ray crystallography, and molecular modeling, in a directed search for new medicinal chemistry leads. In the past few years, the SHAPES strategy has found widespread utility in pharmaceutical research. To illustrate a variety of different implementations of the method, we will focus in this review on recent applications of the SHAPES strategy in several drug discovery programs at Vertex Pharmaceuticals.

Binding Sites↗
PubMedDate not supplied

Computing wiener-type indices for virtual combinatorial libraries generated from heteroatom-containing building blocks.

The expensive and time-consuming process of drug lead discovery is significantly accelerated by efficiently screening molecular libraries with a high structural diversity and selecting subsets of molecules according to their similarity toward specific collections of active compounds. To characterize the molecular similarity/diversity or to quantify the drug-like character of compounds the process of screening virtual and synthetic combinatorial libraries uses various classes of structural descriptors, such as structure keys, fingerprints, graph invariants, and various topological indices computed from atomic connectivities or graph distances. In this paper we present efficient algorithms for the computation of several distance-based topological indices of a molecular graph from the distance invariants of its subgraphs. The procedures utilize vertex- and edge-weighted molecular graphs representing organic compounds containing heteroatoms and multiple bonds. These equations offer an effective way to compute for weighted molecular graphs the Wiener index, even/odd Wiener index, and resistance-distance index. The proposed algorithms are especially efficient in computing distance-based structural descriptors in combinatorial libraries without actually generating the compounds, because only distance-based indices of the building blocks are needed to generate the topological indices of any compound assembled from the building blocks.

Journal Article↗
PubMed2005

Universal newborn hearing screening: are we achieving the Joint Committee on Infant Hearing (JCIH) objectives?

OBJECTIVE: To determine whether a two-stage auditory brainstem response (ABR) Universal Newborn Hearing Screening (UNHS) protocol at an academic medical center has been achieving the Joint Committee on Infant Hearing (JCIH) recommendations for screening all infants, diagnosing hearing loss (HL) within 3 months, and instituting intervention within 6 months. STUDY DESIGN: Retrospective database and chart review in an academic tertiary care hospital. METHODS: A 5-year retrospective review of all newborns screened at our medical center between 1997 to 2001 was performed. Screening was performed by multiple in-hospital postnatal sequential ABR with follow-up outpatient ABR for failures. The protocol called for each newborn to receive at least two separate ABR in-hospital screenings before discharge if the newborn failed the initial screening. For those newborns with extended hospital courses, additional ABR screening were performed randomly in attempt to decrease referral rates at time of discharge. Overall screening population capture rate, referral rate, and false-positive rate were calculated. In addition, HL risk factors, age at diagnosis of HL, and age of onset of intervention were obtained. Cost per diagnosis of HL was calculated as well. RESULTS: The total number screened was 17,602. Seventy-eight (0.44%) were diagnosed with HL, with 62 (79%) in the high-risk population. The frequency of HL was 1 per 811 low-risk neonates versus 1 in 75 meeting high-risk criteria. Overall population capture rate was greater than 99%, referral rate 4.1%, and false-positive rate 3.6%. Mean age at diagnosis was 3.9 months, with mean age at intervention 6.1 months. Cost per diagnosis was estimated at US 5,074 dollars. CONCLUSIONS: Our current UNHS protocol using sequential ABR has been successful in screening virtually all neonates and providing timely intervention. This retrospective review has shown one HL diagnosis for every 811 babies screened without high-risk factors.

Academic Medical Centers↗