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At least 667 records · Page 37Linked to original sources
PubMed2006

Computational approaches to the prediction of blood-brain barrier permeability: A comparative analysis of central nervous system drugs versus secretase inhibitors for Alzheimer's disease.

This review summarizes progress made in the development of fully computational approaches to the prediction of blood-brain barrier (BBB) permeability of small molecules, with a focus on rapid computational methods suitable for the analysis of large compound sets and virtual screening. A comparative analysis using the recently developed Advanced Chemistry Development (ACD/Labs) Inc BBB permeability algorithm for the calculation of logBB values for known Alzheimer's disease medicines, selected central nervous system drugs and new secretase inhibitors for Alzheimer's disease, is presented. The trends in logBB values and the associated physiochemical properties of these agents as they relate to the potential for BBB permeability are also discussed.

Alzheimer Disease↗
PubMed2001

Virtual darwinian drug design: QSAR inverse problem, virtual combinatorial chemistry, and computational screening.

The generation of diversity and its further selection by an external system is a common mechanism for the evolution of the living species and for the current drug design methods. This assumption allows us to label the methods based on generation and selection of molecular diversity as "Darwinian" ones, and to distinguish them from the structure-based, structure-modulation approaches. An example of a Darwinian method is the inverse QSAR. It consists of the computational generation of candidate chemical structures and their selection according to a previously established QSAR model. New trends in the field of combinatorial chemical syntheses comprise the concepts of virtual combinatorial synthesis and virtual or computational screening. Virtual combinatorial synthesis, closely related to inverse QSAR, can be defined as the computational simulation of the generation of new chemical structures by using a combinatorial strategy to generate a virtual library. Virtual screening is the selection of chemical structures having potential desirable properties from a database or virtual library in order to be synthesized and assayed. This review is mainly focused on graph theoretical drug design approaches, but a survey with key references is provided that covers other simulation methods.

Biological Evolution↗
PubMed2003

Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults.

BACKGROUND: We evaluated the performance characteristics of computed tomographic (CT) virtual colonoscopy for the detection of colorectal neoplasia in an average-risk screening population. METHODS: A total of 1233 asymptomatic adults (mean age, 57.8 years) underwent same-day virtual and optical colonoscopy. Radiologists used the three-dimensional endoluminal display for the initial detection of polyps on CT virtual colonoscopy. For the initial examination of each colonic segment, the colonoscopists were unaware of the findings on virtual colonoscopy, which were revealed to them before any subsequent reexamination. The sensitivity and specificity of virtual colonoscopy and the sensitivity of optical colonoscopy were calculated with the use of the findings of the final, unblinded optical colonoscopy as the reference standard. RESULTS: The sensitivity of virtual colonoscopy for adenomatous polyps was 93.8 percent for polyps at least 10 mm in diameter, 93.9 percent for polyps at least 8 mm in diameter, and 88.7 percent for polyps at least 6 mm in diameter. The sensitivity of optical colonoscopy for adenomatous polyps was 87.5 percent, 91.5 percent, and 92.3 percent for the three sizes of polyps, respectively. The specificity of virtual colonoscopy for adenomatous polyps was 96.0 percent for polyps at least 10 mm in diameter, 92.2 percent for polyps at least 8 mm in diameter, and 79.6 percent for polyps at least 6 mm in diameter. Two polyps were malignant; both were detected on virtual colonoscopy, and one of them was missed on optical colonoscopy before the results on virtual colonoscopy were revealed. CONCLUSIONS: CT virtual colonoscopy with the use of a three-dimensional approach is an accurate screening method for the detection of colorectal neoplasia in asymptomatic average-risk adults and compares favorably with optical colonoscopy in terms of the detection of clinically relevant lesions.

Adenoma↗
PubMed2002

[Virtual colonoscopy--chances for a screening procedure?].

In principle, virtual colonoscopy is capable to be used as method for early detection of colorectal cancer (CRC), even if the accuracy of the method and radiation exposure are matters discussion in the radiological community. Virtual colonoscopy is able to detect any pathology which is relevant for early detection of CRC especially when using multislice CT, but also with single slice CT. The diagnosis of small lesions, less than 7 mm in diameter (polyps and flat lesions) is still problematic as it is in conventional colonoscopy. The exposure to x-rays in asymptomatic patients, without any increased risk of developing cancer is highly problematic and should be reduced to a minimum. Using special post processing filters on the volume dataset it can be shown that a tube current of 20 mAs is sufficient without any loss in accuracy. Measurements on the Alderson-phantom showed, that an effective dose exposure of 1.2 mSv is obtained using these reduced mAs values. It has to be differentiated between virtual colonoscopy for early detection of polyps and CRC in individual patients or as a screening examination of a large population. Virtual colonoscopy as a screening examination necessitates reduction of radiation dose, a high degree of automatization in 3D reconstructions as well as the assessment of the entire mucosa. High risk patients, whom refuse fibreoptic colonoscopy should undergo virtual colonoscopy. Virtual colonoscopy has a good chance to become an accepted tool for general screening, if efficient dose reduction, complete visualization of the colon mucosa and automatization of the post processing procedures can be achieved.

Colonic Polyps↗
PubMed2006

Virtual and biomolecular screening converge on a selective agonist for GPR30.

Estrogen is a hormone critical in the development, normal physiology and pathophysiology of numerous human tissues. The effects of estrogen have traditionally been solely ascribed to estrogen receptor alpha (ERalpha) and more recently ERbeta, members of the soluble, nuclear ligand-activated family of transcription factors. We have recently shown that the seven-transmembrane G protein-coupled receptor GPR30 binds estrogen with high affinity and resides in the endoplasmic reticulum, where it activates multiple intracellular signaling pathways. To differentiate between the functions of ERalpha or ERbeta and GPR30, we used a combination of virtual and biomolecular screening to isolate compounds that selectively bind to GPR30. Here we describe the identification of the first GPR30-specific agonist, G-1 (1), capable of activating GPR30 in a complex environment of classical and new estrogen receptors. The development of compounds specific to estrogen receptor family members provides the opportunity to increase our understanding of these receptors and their contribution to estrogen biology.

Animals↗
PubMed2005

New potential antihistaminic compounds. Virtual combinatorial chemistry, computational screening, real synthesis, and pharmacological evaluation.

To study the utility of the virtual combinatorial chemistry coupled with computational screening, a library of amine and urea derivatives was designed by virtual combinatorial synthesis and eventually computationally screened by a mathematical topological model as antihistaminic compounds. The results reveal that virtual combinatorial synthesis and virtual screening together with molecular topology are a powerful tool in the design of new drugs.

Amines↗
PubMedDate not supplied

Identification of a minimal subset of receptor conformations for improved multiple conformation docking and two-step scoring.

Docking and scoring are critical issues in virtual drug screening methods. Fast and reliable methods are required for the prediction of binding affinity especially when applied to a large library of compounds. The implementation of receptor flexibility and refinement of scoring functions for this purpose are extremely challenging in terms of computational speed. Here we propose a knowledge-based multiple-conformation docking method that efficiently accommodates receptor flexibility thus permitting reliable virtual screening of large compound libraries. Starting with a small number of active compounds, a preliminary docking operation is conducted on a large ensemble of receptor conformations to select the minimal subset of receptor conformations that provides a strong correlation between the experimental binding affinity (e.g., Ki, IC50) and the docking score. Only this subset is used for subsequent multiple-conformation docking of the entire data set of library (test) compounds. In conjunction with the multiple-conformation docking procedure, a two-step scoring scheme is employed by which the optimal scoring geometries obtained from the multiple-conformation docking are re-scored by a molecular mechanics energy function including desolvation terms. To demonstrate the feasibility of this approach, we applied this integrated approach to the estrogen receptor alpha (ERalpha) system for which published binding affinity data were available for a series of structurally diverse chemicals. The statistical correlation between docking scores and experimental values was significantly improved from those of single-conformation dockings. This approach led to substantial enrichment of the virtual screening conducted on mixtures of active and inactive ERalpha compounds.

Protein Binding↗
PubMed2006

Comparative molecular surface analysis (CoMSA) for virtual combinatorial library screening of styrylquinoline HIV-1 blocking agents.

We used comparative molecular surface analysis to design molecules for the synthesis as part of the search for new HIV-1 integrase inhibitors. We analyzed the virtual combinatorial library (VCL) constituted from various moieties of styrylquinoline and styrylquinazoline inhibitors. Since imines can be applied in a strategy of dynamic combinatorial chemistry (DCC), we also tested similar compounds in which the -C=N- or -N=C- linker connected the heteroaromatic and aromatic moieties. We then used principal component analysis (PCA) or self-organizing maps (SOM), namely, the Kohonen neural networks to obtain a clustering plot analyzing the diversity of the VCL formed. Previously synthesized compounds of known activity, used as molecular probes, were projected onto this plot, which provided a set of promising virtual drugs. Moreover, we further modified the above mentioned VCL to include the single bond linker -C-N- or -N-C-. This allowed increasing compound stability but expanded also the diversity between the available molecular probes and virtual targets. The application of the CoMSA with SOM indicated important differences between such compounds and active molecular probes. We synthesized such compounds to verify the computational predictions.

Anti-HIV Agents↗
PubMed2006

The virtual crossmatch--a screening tool for sensitized pediatric heart transplant recipients.

Heart transplantation in the setting of human leukocyte antigen (HLA) sensitization is challenging, as a time-consuming prospective crossmatch (XM) may be required, severely limiting the number of potential donors. We evaluated a 'virtual XM', defining a positive virtual XM as the presence of recipient pre-formed anti-HLA antibodies to the prospective donor HLA type, and compared the virtual XM to a standard direct XM. Bead-based flow cytometric analysis was used to identify anti-HLA antibody (Ab) present in a child listed for heart transplantation. Using recipient serum, direct-flow cytometric T- and B-cell XM were run for potential donors against whose HLA type the recipient had specific antibodies (group 1, n = 7) and for potential donors with predicted compatible HLA types by virtual XM (group 2, n = 7). Results were expressed as median channel difference (MCD) between the control and recipient serum. A positive T-cell XM was defined as MCD > 50, whereas MCD > 100 constituted a positive B-cell result. The rate of T-cell reactivity was significantly less in group 2 than in group 1 (29% vs. 100%, p = 0.02); similarly, B-cell reactivity was also less for group 2 (14% vs. 100%, p = 0.005). The virtual XM was 100% sensitive in detecting positive flow cytometric XM results for T and B cells. Although only 72% specific in predicting a negative T-cell XM, and 86% specific for negative B-cell XM, the false negatives were weakly positive and would probably have been clinically acceptable. Currently, potentially suitable donor organs are often declined for lack of a prospective XM; these organs may ultimately be allocated to more distant recipients or perhaps not used at all. While further studies are needed, virtual XM has the potential to improve availability of organs for sensitized patients and improve the overall allocation process.

B-Lymphocytes↗
PubMed2005

Comparative virtual and experimental high-throughput screening for glycogen synthase kinase-3beta inhibitors.

Glycogen synthase kinase-3beta (GSK-3beta) is a serine/threonine kinase that has recently emerged as a key target for neurodegenerative diseases and diabetes. As an initial step of our lead discovery program, we developed a virtual screen to discriminate known GSK-3beta inhibitors and inactive compounds using FlexX, FlexX-Pharm, and FlexE. The maximal enrichment factor (EF = 28) suggests that our protocol identifies potential GSK-3beta inhibitors effectively from large compound collections. The effectiveness of our screening protocol was further investigated by comparative experimental and virtual high-throughput screens (HTSs) performed for the same subset of our corporate library. Enrichment factors, the significantly higher hit rate of virtual screening (12.9%) than that of the HTS (0.55%), and also the comparison of active clusters suggest that our virtual screening protocol is an effective tool in GSK-3beta-based library focusing. Head-to-head comparison of true/false positives and negatives revealed the two approaches to be complementary rather than competitive.

Crystallography, X-Ray↗
PubMed2007

Development of a cathartic-free colorectal cancer screening test using virtual colonoscopy: a feasibility study.

OBJECTIVE: The purpose of our study was to develop a method to subtract barium-labeled stool from the colon using a phantom and to evaluate the performance of the technique in a pilot human population. MATERIALS AND METHODS: A phantom containing 6-mm flat polyps and three types of simulated stool (homogeneous, moderately heterogeneous, and severely heterogeneous) mixed with barium was created, scanned, and tested using three stool subtraction algorithms but no cathartic. Thirty patients with suspected colorectal polyps were studied using stool tagging to determine which was the most effective stool subtraction algorithm. Colonoscopy was the reference standard. Examinations were evaluated blindly using the unsubtracted and 6 weeks later both the unsubtracted and subtracted data sets. RESULTS: A threshold of 200 H and expansion and convolution techniques were the most effective tools for subtracting stool and minimizing artifacts. When applied to the human population, sensitivities using the unsubtracted data sets were 90% (18/20) and 68% (26/38) for polyps > or = 1 cm and > or = 5 mm, respectively. Specificities were 100% (4/4) and 75% (3/4) for polyps > or = 1 cm and > or = 5 mm. For the stool-subtracted data sets, sensitivities were 90% (18/20) and 71% (27/38) for polyps > or = 1 cm and > or = 5 mm. Per patient sensitivities were 88% (15/17) and 77% (20/26) for > or = 1 cm and > or = 5 mm polyps. Specificities were 100% (4/4) for large polyps and 25% (1/4) for smaller polyps. CONCLUSION: Image processing tools combining thresholding, expansion, and convolution were the most useful for stool subtraction. Laxative-free colon examinations using barium for stool labeling can be performed at CT colonography with or without stool subtraction with high accuracy. Further study is warranted.

Algorithms↗
PubMed2006

Inhibition of protein-protein interactions: the discovery of druglike beta-catenin inhibitors by combining virtual and biophysical screening.

The interaction between beta-catenin and Tcf family members is crucial for the Wnt signal transduction pathway, which is commonly mutated in cancer. This interaction extends over a very large surface area (4800 A(2)), and inhibiting such interactions using low molecular weight inhibitors is a challenge. However, protein surfaces frequently contain "hot spots," small patches that are the main mediators of binding affinity. By making tight interactions with a hot spot, a small molecule can compete with a protein. The Tcf3/Tcf4-binding surface on beta-catenin contains a well-defined hot spot around residues K435 and R469. A 17,700 compounds subset of the Pharmacia corporate collection was docked to this hot spot with the QXP program; 22 of the best scoring compounds were put into a biophysical (NMR and ITC) screening funnel, where specific binding to beta-catenin, competition with Tcf4 and finally binding constants were determined. This process led to the discovery of three druglike, low molecular weight Tcf4-competitive compounds with the tightest binder having a K(D) of 450 nM. Our approach can be used in several situations (e.g., when selecting compounds from external collections, when no biochemical functional assay is available, or when no HTS is envisioned), and it may be generally applicable to the identification of inhibitors of protein-protein interactions.

Binding Sites↗
PubMed1999

Molecular diversity and its analysis.

We have recently developed a novel strategy for the rational design of compounds. This 'in silico screening' approach is based on the design and screening of virtual combinatorial libraries. Screening is performed using defined rules derived from a comprehensive description of active and inactive molecules in a relevant learning set. This strategy allows the development of potential ligands without the necessity of any knowledge of the 3D-structure of the target receptor. Key to the success of such methods is the quality of the information being processed, in particular, the diversity of the data in the context of the molecular population in the libraries concerned. Here, we review the problem of data diversity, its definition and its analysis using a new software tool, named Diverser.

Journal Article↗