44,763 research outputs found
Spherical harmonics coeffcients for ligand-based virtual screening of cyclooxygenase inhibitors
Background: Molecular descriptors are essential for many applications in computational chemistry, such as ligand-based similarity searching. Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening. Methodology/Principal Findings: We introduce and validate a partially rotation-invariant three-dimensional molecular shape descriptor based on the norm of spherical harmonics expansion coefficients. Using this molecular representation, we parameterize molecular surfaces, i.e., isosurfaces of spatial molecular property distributions. We validate the shape descriptor in a comprehensive retrospective virtual screening experiment. In a prospective study, we virtually screen a large compound library for cyclooxygenase inhibitors, using a self-organizing map as a pre-filter and the shape descriptor for candidate prioritization. Conclusions/Significance: 12 compounds were tested in vitro for direct enzyme inhibition and in a whole blood assay. Active compounds containing a triazole scaffold were identified as direct cyclooxygenase-1 inhibitors. This outcome corroborates the usefulness of spherical harmonics for representation of molecular shape in virtual screening of large compound collections. The combination of pharmacophore and shape-based filtering of screening candidates proved to be a straightforward approach to finding novel bioactive chemotypes with minimal experimental effort
Geodesics on the manifold of multivariate generalized Gaussian distributions with an application to multicomponent texture discrimination
We consider the Rao geodesic distance (GD) based on the Fisher information as a similarity measure on the manifold of zero-mean multivariate generalized Gaussian distributions (MGGD). The MGGD is shown to be an adequate model for the heavy-tailed wavelet statistics in multicomponent images, such as color or multispectral images. We discuss the estimation of MGGD parameters using various methods. We apply the GD between MGGDs to color texture discrimination in several classification experiments, taking into account the correlation structure between the spectral bands in the wavelet domain. We compare the performance, both in terms of texture discrimination capability and computational load, of the GD and the Kullback-Leibler divergence (KLD). Likewise, both uni- and multivariate generalized Gaussian models are evaluated, characterized by a fixed or a variable shape parameter. The modeling of the interband correlation significantly improves classification efficiency, while the GD is shown to consistently outperform the KLD as a similarity measure
Automatic generation of alignments for 3D QSAR analyses
Many 3D QSAR methods require the alignment of the molecules in a dataset, which can require a fair amount of manual effort in deciding upon a rational basis for the superposition. This paper describes the use of FBSS, a pro-ram for field-based similarity searching in chemical databases, for generating such alignments automatically. The CoMFA and CoMSIA experiments with several literature datasets show that the QSAR models resulting from the FBSS alignments are broadly comparable in predictive performance with the models resulting from manual alignments
Computerized Analysis of Magnetic Resonance Images to Study Cerebral Anatomy in Developing Neonates
The study of cerebral anatomy in developing neonates is of great importance for
the understanding of brain development during the early period of life. This
dissertation therefore focuses on three challenges in the modelling of cerebral
anatomy in neonates during brain development. The methods that have been
developed all use Magnetic Resonance Images (MRI) as source data.
To facilitate study of vascular development in the neonatal period, a set of image
analysis algorithms are developed to automatically extract and model cerebral
vessel trees. The whole process consists of cerebral vessel tracking from
automatically placed seed points, vessel tree generation, and vasculature
registration and matching. These algorithms have been tested on clinical Time-of-
Flight (TOF) MR angiographic datasets.
To facilitate study of the neonatal cortex a complete cerebral cortex segmentation
and reconstruction pipeline has been developed. Segmentation of the neonatal
cortex is not effectively done by existing algorithms designed for the adult brain
because the contrast between grey and white matter is reversed. This causes pixels
containing tissue mixtures to be incorrectly labelled by conventional methods. The
neonatal cortical segmentation method that has been developed is based on a novel
expectation-maximization (EM) method with explicit correction for mislabelled
partial volume voxels. Based on the resulting cortical segmentation, an implicit
surface evolution technique is adopted for the reconstruction of the cortex in
neonates. The performance of the method is investigated by performing a detailed
landmark study.
To facilitate study of cortical development, a cortical surface registration algorithm
for aligning the cortical surface is developed. The method first inflates extracted
cortical surfaces and then performs a non-rigid surface registration using free-form
deformations (FFDs) to remove residual alignment. Validation experiments using
data labelled by an expert observer demonstrate that the method can capture local
changes and follow the growth of specific sulcus
PVR: Patch-to-Volume Reconstruction for Large Area Motion Correction of Fetal MRI
In this paper we present a novel method for the correction of motion
artifacts that are present in fetal Magnetic Resonance Imaging (MRI) scans of
the whole uterus. Contrary to current slice-to-volume registration (SVR)
methods, requiring an inflexible anatomical enclosure of a single investigated
organ, the proposed patch-to-volume reconstruction (PVR) approach is able to
reconstruct a large field of view of non-rigidly deforming structures. It
relaxes rigid motion assumptions by introducing a specific amount of redundant
information that is exploited with parallelized patch-wise optimization,
super-resolution, and automatic outlier rejection. We further describe and
provide an efficient parallel implementation of PVR allowing its execution
within reasonable time on commercially available graphics processing units
(GPU), enabling its use in the clinical practice. We evaluate PVR's
computational overhead compared to standard methods and observe improved
reconstruction accuracy in presence of affine motion artifacts of approximately
30% compared to conventional SVR in synthetic experiments. Furthermore, we have
evaluated our method qualitatively and quantitatively on real fetal MRI data
subject to maternal breathing and sudden fetal movements. We evaluate
peak-signal-to-noise ratio (PSNR), structural similarity index (SSIM), and
cross correlation (CC) with respect to the originally acquired data and provide
a method for visual inspection of reconstruction uncertainty. With these
experiments we demonstrate successful application of PVR motion compensation to
the whole uterus, the human fetus, and the human placenta.Comment: 10 pages, 13 figures, submitted to IEEE Transactions on Medical
Imaging. v2: wadded funders acknowledgements to preprin
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Quantitative surface field analysis: learning causal models to predict ligand binding affinity and pose.
We introduce the QuanSA method for inducing physically meaningful field-based models of ligand binding pockets based on structure-activity data alone. The method is closely related to the QMOD approach, substituting a learned scoring field for a pocket constructed of molecular fragments. The problem of mutual ligand alignment is addressed in a general way, and optimal model parameters and ligand poses are identified through multiple-instance machine learning. We provide algorithmic details along with performance results on sixteen structure-activity data sets covering many pharmaceutically relevant targets. In particular, we show how models initially induced from small data sets can extrapolatively identify potent new ligands with novel underlying scaffolds with very high specificity. Further, we show that combining predictions from QuanSA models with those from physics-based simulation approaches is synergistic. QuanSA predictions yield binding affinities, explicit estimates of ligand strain, associated ligand pose families, and estimates of structural novelty and confidence. The method is applicable for fine-grained lead optimization as well as potent new lead identification
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