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PubMedDate not supplied

Library design using BCUT chemistry-space descriptors and multiple four-point pharmacophore fingerprints: simultaneous optimization and structure-based diversity.

New applications of fingerprints of multiple potential 4-point three-dimensional (3D) pharmacophores in combinatorial library design and virtual screening are presented. Preliminary results demonstrating the feasibility of a simulated annealing process for combinatorial reagent selection that concurrently optimizes product diversity in BCUT chemistry space and in terms of unique 4-point pharmacophores are discussed, and the advantage of using a customized chemistry-space derived for the library design is demonstrated. In addition, an extension to the multiple pharmacophore method for structure-based design that uses the shape of the target site as an additional constraint is presented. This development enables the docking process to be quantified in terms of the number and identities of the pharmacophoric hypotheses that can be matched by a compound or a library of compounds. The design of an example combinatorial library based on the Ugi condensation reaction and a serine protease active site is described.

Binding Sites↗
PubMed2001

Theoretical hydrogen bonding parameters for drug design.

Hydrogen bonding interactions play a major role in many chemical and biological processes. This article describes the development of a method for the quantitative estimation of the hydrogen-bonding donor strengths of OH/NH moieties and of the hydrogen bonding acceptor strengths of O/N atoms in different chemical structures. The method is based on the correlation of experimentally observed hydrogen-bonding strengths with quantum-mechanical derived properties, calculated on the acceptor atom (for hydrogen-bond acceptors) and on the heavy atom attached to the donor hydrogen (for hydrogen-bond donors). The properties giving the best correlation with the experimental hydrogen bonding scales were electrophilic superdelocalizability and self-atom polarizability. The best equations found have been implemented in a Web-based tool for hydrogen-bond strength prediction.

Computer Graphics↗
PubMed2001

Crystallographic autostereograms.

Perspective drawings of crystal structures can be presented as autostereograms (or single-image stereograms), and their performance for in-depth perception is similar or even more advantageous than of stereopairs. The autostereograms offer a convenient means for realistic insight into crystal structures without excessive size reduction of their drawings, as required when preparing stereopairs; thus structures either as simple as elements or as complex as proteins can be illustrated in enhanced resolution. The mathematical background and guidelines for preparing crystallographic autostereograms are described.

Computer Graphics↗
PubMed2002

Molecular modelling of the differential interaction between several non-steroidal anti-inflammatory drugs and human prostaglandin endoperoxide H synthase-2 (h-PGHS-2).

The prostaglandin endoperoxide H synthase-1 (PGHS-1) and prostaglandin endoperoxide H synthase-2 (PGHS-2) are the targets of non-steroidal anti-inflammatory drugs (NSAIDs). The high degree of selectivity for inhibition of PGHS-2 shown by certain compounds appears to stem from two mechanisms (time-dependent, time-independent inhibition) by which they interact with each isoform. Molecular models of the complexes between indomethacin, fenamates, 2-phenylpropionic acids and the selective cyclooxygenase-2 (COX-2) inhibitors, with the cyclooxygenase active site of human PGHS-2 have been built by combining homology modelling, conformational searching and automated docking techniques. The stability of the resulting complexes has been assessed by molecular dynamics simulations combined with extended linear response calculations. The results allow us to identify regions of biological significance consistent with both X-ray crystallographic and kinetic results. The selective PGHS-2 inhibitors exploit the extra space of a side-pocket in the active site of PGHS-2 that is not found in PGHS-1. The results obtained point out a marked relationship between the experimental affinity and the electrostatic interaction energy alone for a series of NSAIDs. Analysis of the structural and the energetic data provides evidence supporting that network of hydrogen bonds between Tyr355, Glu524, Arg120 and Arg513 might be involved in mediating the binding of the time-dependent inhibitors of PGHS-2.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

A novel approach for identifying the surface atoms of macromolecules.

A significant number of atoms lie buried beneath the "molecular surface" of proteins and other biologic macromolecules. Interactions between ligands and these macromolecules are dominated by interactions with the "surface atoms". Although interactions with the "buried" or interior atoms of the macromolecule certainly contribute to the total intermolecular interaction energy, many computer-assisted drug design (CADD) strategies can benefit from the identification of those atoms "on the surface" of proteins and other macromolecules. We have developed a simple, yet novel method to distinguish the surface atoms of macromolecules from the interior atoms which is based on computing the atomic contributions to the solvent-accessible surface (SAS) area. This report describes that method and demonstrates that it compares very favorably with four alternative methods.

Computer Graphics↗
PubMed2003

Analysis and optimization of structure-based virtual screening protocols (1): exploration of ligand conformational sampling techniques.

Ligand conformational flexibility has long been recognized as an important issue in virtual screening (VS). To this end, a number of different methodologies have been adapted to tackle the problem. Many of said techniques were originally designed for ligand derived pharmacophore screens, but have subsequently been fashioned for application within structure-based virtual screening (SVS). A popular adaptation is the pre-calculation of diverse ligand conformations for subsequent docking in target active sites. In this paper, we study a number of the software programs currently being used in conformer generation, analyzing their ability to regenerate known ligand binding conformations. The implications of these studies are discussed, from the perspective of VS in general and SVS in particular.

Computational Biology↗
PubMed2003

Analysis and optimization of structure-based virtual screening protocols. 2. Examination of docked ligand orientation sampling methodology: mapping a pharmacophore for success.

An important element of any structure-based virtual screening (SVS) technique is the method used to orient the ligands in the target active site. This has been a somewhat overlooked issue in recent SVS validation studies, with the assumption being made that the performance of an algorithm for a given set of orientation sampling settings will be representative for the general behavior of said technique. Here, we analyze five different SVS targets using a variety of sampling paradigms within the DOCK, GOLD and PROMETHEUS programs over a data set of approximately 10,000 noise compounds, combined with data sets containing multiple active compounds. These sets have been broken down by chemotype, with chemotype hit rate used to provide a measure of enrichment with a potentially improved relevance to real world SVS experiments. The variability in enrichment results produced by different sampling paradigms is illustrated, as is the utility of using pharmacophores to constrain sampling to regions that reflect known structural biology. The difference in results when comparing chemotype with compound hit rates is also highlighted.

Binding Sites↗
PubMed2003

Analysis and optimization of structure-based virtual screening protocols. (3). New methods and old problems in scoring function design.

Scoring function research remains a primary focus of current structure-based virtual screening (SVS) technology development. Here, we present an alternative method for scoring function design that attempts to combine crystallographic structural information with data derived from directly within SVS calculations. The technique utilizes a genetic algorithm (GA) to optimize functions based on binding property data derived from multiple virtual screening calculations. These calculations are undertaken on protein data bank (PDB) complex active sites using ligands of known binding mode in conjunction with "noise" compounds. The advantages of such an approach are that the function does not rely on assay data and that it can potentially use the "noise" binding data to recognize the sub-optimal docking interactions inherent in SVS calculations. Initial efforts in technique exploration using DOCK are presented, with comparisons made to existing DOCK scoring functions. An analysis of the problems inherent to scoring function development is also made, including issues in dataset creation and limitations in descriptor utility when viewed from the perspective of docking mode resolution. The future directions such studies might take are also discussed in detail.

Algorithms↗
PubMed1997

Internal motions and hydration of sucrose in a diluted water solution.

This paper represents a synthesis of our most recent work on the hydration, internal and overall dynamics of sucrose in a diluted water solution. The studies were carried out as a total ensemble of 1.2 nanosecond condensed phase molecular dynamics trajectories. In this study the focus is on a 500 ps trajectory starting with the solute in the crystalline conformation. The presence of water was found to significantly alter the accessible conformational space of the solute. All potential intra-molecular hydrogen bonds were found to be exchanged to surrounding water molecules and the simulations suggest that the sucrose conformation is stabilized by the dynamic presence of two interring bridging water molecules: O-2g...Ow...O-3f and O-2g...Ow...O-lf. The overall shift in conformation of the solute induced by the presence of water was found to improve the theoretical models of experimental traits. It is demonstrated that the hydration structure and the internal and overall motions of sucrose compare extremely well with NMR data such as glycosidic heteronuclear coupling constants and the molecular tumbling time, with X-ray data of two partially hydrated sucrose structures in a protein complex and with translational diffusion coefficients and hydration numbers established from experimental studies.

Carbohydrate Conformation↗
PubMed1997

A quantitative investigation of the transannular amine-ketone (N...C=O) interaction in medium-sized heterocycles.

The transannular N...C=O interaction in several medium-sized heterocycles has been investigated by force-field methods. Conformational searching has been performed at the molecular mechanics level using different methods and the conformers so generated have been reoptimized at RHF/6-31G(d). For selected conformers, N...C distances are reported, together with transannular bond orders and atomic charges. Good agreement with available X-ray crystallographic data is obtained for the transannular bond distance in cryptopine. Changes in the partial atomic charges derived from the electrostatic potential provide good support for the donor-acceptor model of transannular interactions. Partial charges derived with other methods do not give satisfactory results. Some force fields do not reproduce the transannular interaction very well. This is demonstrated and rationalized, and modifications are suggested and tested for these force fields with good results when comparing diagnostic geometric features with X-ray data.

Alkaloids↗
PubMed1997

Modeling of the three-dimensional structure of the human melanocortin 1 receptor, using an automated method and docking of a rigid cyclic melanocyte-stimulating hormone core peptide.

A model is presented of the melanocortin 1 receptor (MC1R), constructed by use of an unbiased, objective method. The model is created directly from data derived from multiple sequence analysis, a low-resolution EM-projection map of rhodopsin, and the approximate membrane thickness. The model agrees well with available data concerning natural mutations of MC1Rs occurring in different species. A model is also presented of the most rigid ligand for this receptor, the cyclic pentapeptide cHFRWG, shown docked in the receptor model. The receptor-ligand complex model agrees well with available experimental data. The ligand is located between transmembrane region 1 (TM1), TM2, TM3, TM6, and TM7 of the receptor. Multiple interactions occur between ligand and receptor, including interactions with Leu-48 (TM1), Ser-52 (TM1), Glu-55 (TM1), Asn-91 (TM2), Glu-94 (TM2), Thr-95 (TM2) Ile-98 (TM2), Asp-121 (TM3), Thr-124 (TM3), Phe-257 (TM6), Phe-283 (TM7), Asn-290 (TM7), and Asp-294 (TM7) of the receptor.

Amino Acid Sequence↗
PubMed1997

Simulation of alternative binding modes in a structure-based QSAR study of HIV-1 protease inhibitors.

We have used a published set of inhibitors of HIV-1 protease to build a COMBINE-type structure-based QSAR model with good predictive ability (r2 = 0.90, q2 = 0.69). Since the compounds in the training series exhibit most of their structural variability on one-half of the pseudosymmetrical binding cavity and only one binding orientation was explored for each molecule, the model describes mainly the effect of the structural changes on interactions involving only one-half of the binding cavity (pockets S1' and S2'). Thus, the model cannot be expected to give accurate predictions for new compounds exhibiting structural variation in both halves. The model does in fact show a tendency to underpredict slightly the biological activity of the molecules in the external test set. In an attempt to improve the quality of the model, both possible orientations of the ligands are now considered so that structural variation takes place in all binding pockets. One possibility would have been to build an additional set of complexes with the inhibitors docked in a reversed orientation. The alternative we have explored, however, consists of manipulating the data matrix describing the interaction energies so that each row is duplicated and the order of the variables in the duplicated rows is swapped between subunits. This simple approach has produced a new model that is similar in quality to the original model (r2 = 0.89, q2 = 0.64) but lacks the tendency to underpredict the activity of the compounds in the external set. Moreover, since equivalent residues are assigned equivalent weights, the model is insensitive to ligand orientation and is easier to interpret.

Artificial Intelligence↗
PubMed2003

A specialized plug-in software module for computer-aided quantitative measurement of medical images.

This paper presents a specialized system for quantitative measurement of medical images. Using Visual C++, we developed a computer-aided software based on Image-Pro Plus (IPP), a software development platform. When transferred to the hard disk of a computer by an MVPCI-V3A frame grabber, medical images can be automatically processed by our own IPP plug-in for immunohistochemical analysis, cytomorphological measurement and blood vessel segmentation. In 34 clinical studies, the system has shown its high stability, reliability and ease of utility.

Algorithms↗
PubMed2000

T-snakes: topology adaptive snakes.

We present a new class of deformable contours (snakes) and apply them to the segmentation of medical images. Our snakes are defined in terms of an affine cell image decomposition (ACID). The 'snakes in ACID' framework significantly extends conventional snakes, enabling topological flexibility among other features. The resulting topology adaptive snakes, or 'T-snakes', can be used to segment some of the most complex-shaped biological structures from medical images in an efficient and highly automated manner.

Brain↗
PubMed2002

Algorithmic tools for real-time microsurgery simulation.

Today, there is growing interest in computer surgical simulation to enhance surgeons' training. This paper presents a simulation system based on novel algorithms for animating instruments interacting with deformable tissue in real-time. The focus is on computing the deformation of a tissue subject to external forces, and detecting collisions among deformable and rigid objects. To achieve real-time performance, the algorithms take advantage of several characteristics of surgical training: (1) visual realism is more important than accurate, patient-specific simulation; (2) most tissue deformations are local; (3) human-body tissues are well damped; and (4) surgical instruments have relatively slow motions. Each key algorithm is described in detail and quantitative performance-evaluation results are given. The specific application considered in this paper is microsurgery, in which the user repairs a virtual severed blood vessel using forceps and a suture (micro-anastomosis). Microsurgery makes it possible to demonstrate several facets of the simulation algorithms, including the deformations of the blood vessel and the suture, and the collisions and interactions between the vessel, the forceps, and the suture. Validation of the overall microsurgery system is based on subjective analysis of the simulation's visual realism by different users.

Algorithms↗
PubMed2002

Tracking of a bronchoscope using epipolar geometry analysis and intensity-based image registration of real and virtual endoscopic images.

This paper describes a method for tracking the camera motion of a flexible endoscope, in particular a bronchoscope, using epipolar geometry analysis and intensity-based image registration. The method proposed here does not use a positional sensor attached to the endoscope. Instead, it tracks camera motion using real endoscopic (RE) video images obtained at the time of the procedure and X-ray CT images acquired before the endoscopic examination. A virtual endoscope system (VES) is used for generating virtual endoscopic (VE) images. The basic idea of this tracking method is to find the viewpoint and view direction of the VES that maximizes a similarity measure between the VE and RE images. To assist the parameter search process, camera motion is also computed directly from epipolar geometry analysis of the RE video images. The complete method consists of two steps: (a) rough estimation using epipolar geometry analysis and (b) precise estimation using intensity-based image registration. In the rough registration process, the method computes camera motion from optical flow patterns between two consecutive RE video image frames using epipolar geometry analysis. In the image registration stage, we search for the VES viewing parameters that generate the VE image that is most similar to the current RE image. The correlation coefficient and the mean square intensity difference are used for measuring image similarity. The result obtained in the rough estimation process is used for restricting the parameter search area. We applied the method to bronchoscopic video image data from three patients who had chest CT images. The method successfully tracked camera motion for about 600 consecutive frames in the best case. Visual inspection suggests that the tracking is sufficiently accurate for clinical use. Tracking results obtained by performing the method without the epipolar geometry analysis step were substantially worse. Although the method required about 20 s to process one frame, the results demonstrate the potential of image-based tracking for use in an endoscope navigation system.

Algorithms↗
PubMed1999

Three-dimensional computer vision for tooth restoration.

If a person with carious lesions needs or requests crowns or inlays, these dental fillings have to be manufactured for each tooth and each person individually. We survey computer vision techniques which can be used to automate this process. We introduce three particular applications which are concerned with the reconstruction of surface information. The first one aims at building up a database of normalized depth images of posterior teeth and at extracting characteristic features from these images. In the second application, a given occlusal surface of a posterior tooth with a prepared cavity is digitally reconstructed using an intact model tooth from a given database. The calculated surface data can then be used for automatic milling of a dental prosthesis, e.g. from a preshaped ceramic block. In the third application a hand-made provisoric wax inlay or crown can be digitally scanned by a laser sensor and copied three dimensionally into a different material such as ceramic. The results are converted to a format required by the computer-integrated manufacturing (CIM) system for automatic milling.

Adolescent↗
PubMed1999

Incorporating a statistically based shape model into a system for computer-assisted anterior cruciate ligament surgery.

This paper addresses the problem of extrapolating very sparse three-dimensional (3-D) data to obtain a complete surface representation. A new method that uses statistical shape models is proposed and its application to computer-assisted anterior cruciate ligament (ACL) reconstruction is detailed. The rupture of the ACL has become one of the most common knee injuries. One problem during reconstruction is to find the optimal attachment points for the graft. Therefore a system for computer-assisted reconstruction of the ACL has been proposed by TIMC laboratory. During surgery the surgeon collects several data points on the tibial and femoral joint surface with a 3-D localizer system. These 3-D data are used to find those attachment points resulting in a low anisometry of the graft, while preventing impingement between the graft and the femoral notch. As the collected data points only cover a small surface patch of the femur, it is desirable to extrapolate these data to also have a visualization in those areas where no data points are available. A sufficiently good approximation of the actual femur by the model would further allow us to better deal with the notch impingement problem of the graft. The chosen approach is to fit a deformable model to the data points, it can be subdivided into two steps, constructing the model and fitting this model to the data. To incorporate a priori knowledge into the model, the allowed deformations are determined by the statistics of the shape variation of a set of training objects. Matching the training objects together is obtained by elastic registration of surface points using octree splines. The fitting process of the sparse intra-operative data with the statistical model results in a non-linear multi-dimensional function minimization. A hybrid search strategy combining local and global methods is used to avoid local minima. First experimental results with a model generated from 10 femurs are presented, including fitting of the model with both simulated and real intra-operative data.

Anisotropy↗