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At least 1,513 records · Page 84Linked to original sources
PubMed1990

Theoretical design of novel, 4 base pair selective derivatives of mitoxantrone.

Mitoxantrone (MTX) is a recently synthesized antitumor intercalative molecule, currently in use in chemotherapy. Previous theoretical computations showed that the base pair selectivity of MTX is limited to the sole two base-pair sequence making up the intercalation site. In order to further extend the recognition site, we undertook, by means of theoretical computations, the design of novel MTX derivatives, in which the terminal hydroxyl group of each side chain is esterified with oligopeptides. We compare in the present study the binding affinities of two derivatives, depsiGly-Lys(D) and depsiGly-Gly-Orn(L), for the palindromic sequences d(CCCGGG)2, d(GCCGGC)2, d(GGCGCC)2, and d(CGCGCG)2. Major groove binding of the oligopeptide arms was shown to be significantly more favourable than either minor groove binding, or binding to the sole phosphate groups. With the two arms adopting two antiparallel directions, two distinct arrangements were investigated in the major groove: (a) the two oligopeptides are brought closer together by means of two hydrogen bonds involving the backbone of their second residue in a beta-sheet like arrangement; (b) the two arms are remote from each other so as to reduce their mutual electrostatic repulsion. Whatever the disposition, the optimal binding configurations were invariably found to be those in which the cationic side chains of the terminal residues chelate N7/O6 of two successive guanines, whenever present on a given strand. A distinct energetical preference for arrangement (a) was obtained with the depsiGly-Gly-Orn(L) derivative. Replacement of the central Gly residue by a Cys one, as in the sequence depsiGly-Cys-Orn(L), was proposed subsequently, so as to further stabilize such a beta-sheet arrangement by means of a disulfide bridge between the two Cys residues. The two investigated compounds were shown to preferentially bind sequences d(CCCGGG)2 and d(GCCGGC)2, with a tetrameric core CCGG rather than sequences d(GGCGCC)2 and d(CGCGCG)2, with a tetrameric core GCGC.

Amino Acid Sequence↗
PubMed2005

Discovery of HIV-1 integrase inhibitors through a novel combination of ligand and structure-based drug design.

Over the past 10 years, classical computer-aided molecular design methods have not been frequently applied for the discovery of novel HIV-1 integrase (IN) inhibitors, due to the intrinsic challenges that this enzyme presents. Therefore, a novel approach that combines the chemical information of known integrase inhibitors with the enzyme's detailed 3D structure in a stepwise fashion is proposed: (I) use of a pharmacophore model (PM), which takes into account in a weighted fashion the chemical features of known ligands, in analogous manner to the to search the Maybridge and the NCI 3D databases; (II) drug-likeness optimization; (III) virtual high-throughput screening of the hits matching the PM query against 1QS4 wild-type IN structure using different Docking/Scoring combinations; (IV) visual inspection and selection of the hits in function of: binding free energies; binding mode type within the active site; retrieval among the best 20% hits in more than 6 Docking/Scoring protocols at the same time. This approach aims at a rational selection of new potential HIV-1 integrase inhibitors.

Computer Simulation↗
PubMed1998

The role of pharmacokinetic modelling and computer simulation in drug formulation design.

The purpose of this study is to develop a formulation for a once-a-day peroral application with controlled release of nitrendipine. The second aim of the study is to define by the use of modelling and computer simulation those critical points in the development of the formulation, the knowledge and controlling of which brings a rationalisation in the sense of time and material.

Administration, Oral↗
PubMed1994

Crystal-structure-based design and synthesis of novel C-terminal inhibitors of HIV protease.

The X-ray crystal-structure-based design, synthesis, computational evaluation, and activity of a novel class of HIV protease inhibitors are described. The initial lead compounds 2 and 3 were designed by modeling replacement groups for the C-terminal Val-Val-OCH3 of a known hydroxyethylene inhibitor into the active site of the reported crystal structure of HIV protease complexed with MVT-101. The lead compound 2 was found to be a modest inhibitor with a Ki = 1.67 microM. The X-ray crystal structure of compound 2 complexed with HIV protease was solved and used for subsequent design. The lead compound 3 was found to be a more potent inhibitor with Ki = 0.2 microM, and the structure of it complexed with HIV protease was also solved and used for subsequent design. Modification of both the C-terminus and N-terminus of indole 3 resulted in compounds with Ki = 30 nM. Using the crystal structure of compounds 2 and 3 with HIV protease as a starting point, the thermodynamic cycle perturbation molecular dynamics method was applied to a select group of compounds in order to test the accuracy of this type of computation within a series of closely related compounds.

Crystallography, X-Ray↗
PubMed2006

Haptic applications for molecular structure manipulation.

We describe the application of haptic technology to enhance the information available in chemical systems, specifically related to computational drug design. These methods are designed to build upon the visual information presented by molecular viewers and add the sensation of touch, or force feedback. The addition of sensory input can aid in the analysis of molecular structures and the understanding of intermolecular interactions by delivering chemically relevant forces to the end user.

Computer Graphics↗
PubMedDate not supplied

Chemoinformatics methods for systematic comparison of molecules from natural and synthetic sources and design of hybrid libraries.

Until recently, the field of diversity and library design has more or less ignored natural products as a compound source. This is probably due to at least two reasons. First, combinatorial and reaction-based approaches have been major focal points in the early days of computational library design. In addition, a widespread view is that natural products are often highly complex and not amenable to medicinal chemistry efforts. This contribution introduces recent computational approaches to systematically analyze natural molecules and bridge the gap between natural products and synthetic chemistry programs. Large scale comparisons of natural and synthetic molecules are discussed as well as studies designed to identify 'synthetic mimics' of natural products with specific activity. In addition, a concept for the design of natural/synthetic hybrid libraries is introduced. Although research in this area is still in its early stages, an important lesson to be learned from computational analyses is that there is no need to a priori 'shy away' from natural products as a source for molecular design.

Biological Factors↗
PubMed2002

Chemoinformatics methods for systematic comparison of molecules from natural and synthetic sources and design of hybrid libraries.

Until recently, the field of diversity and library design has more or less ignored natural products as a compound source. This is probably due to at least two reasons. First, combinatorial and reaction-based approaches have been major focal points in the early days of computational library design. In addition, a widespread view is that natural products are often highly complex and not amenable to medicinal chemistry efforts. This contribution introduces recent computational approaches to systematically analyze natural molecules and bridge the gap between natural products and synthetic chemistry programs. Large scale comparisons of natural and synthetic molecules are discussed as well as studies designed to identify 'synthetic mimics' of natural products with specific activity. In addition, a concept for the design of natural/synthetic hybrid libraries is introduced. Although research in this area is still in its early stages, an important lesson to be learned from computational analyses is that there is no need to a priori 'shy away' from natural products as a source for molecular design.

Biological Factors↗
PubMed2002

Design and implementation of a computer decision support system for the diagnosis and management of dementia syndromes in primary care.

BACKGROUND: Diagnosis and management of dementia is a complex process and primary care physicians are under-equipped to deal with uncertainties in the provision of optimal care for the patient. OBJECTIVE: To develop a computer decision support system (CDSS) which could assist physicians with diagnosis and management and improve patient care. METHODS: A design group including general practitioners derived logic pathways for diagnosis and management of dementia and validated them with a multiprofessional expert group. Logic pathways were used to construct a comprehensive CDSS rendered as a series of expert consultations. The CDSS was inserted into commercially available GP systems and bench and field-tested. RESULTS: The complexity of dementia diagnosis and management can be captured in logic pathways which can be expressed as decision trees within existing electronic patient records. The resulting CDSS appears useable in routine practice. CONCLUSION: The impact of this CDSS will be evaluated in a randomised controlled trial of educational interventions in primary care.

Aged↗
PubMed1992

Computer models of hearing aid transducers for integrated circuit design.

Electronic circuit modeling using computer-based simulation tools is well established and device models are available for common electronic components. However, acoustic models of audio transducers for use during integrated circuit design are not readily available. This causes difficulty for designers of audio amplifiers, and increases the uncertainties of a successful silicon integration of a circuit design. This paper reports on a technique for the creation of electroacoustic models of hearing aid microphones and receivers that can be connected to an amplifier under design, and incorporated into PSPICE simulations. Verification of the technique and models was performed by comparing measured frequency response data with graphs created by PSPICE modeling. The conclusions were that the method developed for creating these models, and the models themselves, were accurate enough to be used for acoustic simulations of frequency response performance during amplifier design, and gave results comparable to data obtained from breadboard measurements of the same circuits.

Computer Simulation↗
PubMed1978

Split xenon detector for tomochemistry in computed tomography.

The design of a split high-pressure xenon detector array for tomochemistry in computed tomography (CT) is described. Each detector produces a signal from the front primarily due to low energy photons and a signal from the back primarily due to high energy photons. Two methods are described whereby these signals are used to determine the photoelectric and Compton coefficients. From these, the electron density and average atomic number can be determined for each pixel in the image. These methods were tested by computer simulations of scans of a simple phantom, and the resulting Compton and photoelectric images are presented and compared with a conventional CT image. It was found that electron density and atomic number can be determined to an accuracy of better than 4%. The sensitivity to noise was studied, and it was found that the standard deviation of the mean of a 5 X 5 pixel region in the conventional image is about a factor of 3 lower than in the same region in the Compton image and about a factor of 40 lower than in the photoelectric image.

Humans↗
PubMed1999

Detrimental kinematics of a flat on flat total condylar knee arthroplasty.

Fourteen subjects having a flat on flat condylar posterior cruciate retaining total knee arthroplasty were evaluated under different in vivo weightbearing conditions, with six performing a deep knee bend and eight walking at normal gait. An interactive model fitting algorithm was used to convert two-dimensional fluoroscopic images into three-dimensional computer aided design solid model images. The femorotibial contact positions for the medial and lateral condyle started posterior at full extension. With a deep knee bend the lateral condyle acted as a pivot, and the medial condyle slid in the anterior direction. Five of six had lateral condyle liftoff (maximum 1.6 mm) and abnormal positive screw home motion was seen from 0 degree to 90 degrees flexion. During gait, all femorotibial contact positions were posterior in extension and throughout the cycle. Six of eight patients experienced lateral condyle liftoff (maximum 3.5 mm), but minimal screw home motion was seen. Abnormal medial condyle posteroanterior sliding, lateral condyle liftoff, and erratic screw home motion may be related to abnormal wear characteristics of this flat on flat condylar design.

Algorithms↗
PubMed1988

D-optimal design applied to binding saturation curves of an enkephalin analog in rat brain.

The D-optimal design, a minimal sample design that minimizes the volume of the joint confidence region for the parameters, was used to evaluate binding parameters in a saturation curve with a view to reducing the number of experimental points without loosing accuracy in binding parameter estimates. Binding saturation experiments were performed in rat brain crude membrane preparations with the opioid mu-selective ligand [3H]-[D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO), using a sequential procedure. The first experiment consisted of a wide-range saturation curve, which confirmed that [3H]-DAGO binds only one class of specific sites and non-specific sites, and gave information on the experimental range and a first estimate of binding affinity (Ka), capacity (Bmax) and non-specific constant (k). On this basis the D-optimal design was computed and sequential experiments were performed each covering a wide-range traditional saturation curve, the D-optimal design and a splitting of the D-optimal design with the addition of 2 points (+/- 15% of the central point). No appreciable differences were obtained with these designs in parameter estimates and their accuracy. Thus sequential experiments based on D-optimal design seem a valid method for accurate determination of binding parameters, using far fewer points with no loss in parameter estimation accuracy.

Animals↗
PubMed2002

[The integrated management software of primary care,a tool for analysing indicators of use].

OBJECTIVES: To analyse the indicators of use in the Gran Canaria Health Area. To characterise over-users so that the primary care team can take corrective measures. To design a computer tool giving appropriate useful information to the management, that can be directly put into practice in primary care. DESIGN: Retrospective descriptive study. SATTING: Gran Canaria Health Area. Hierarchical descent in the analysis of data in the base health area and family care unit, in the year 2000. PARTICIPANTS: Users of the Canaries Health Service registered on the individual health card data base. MAIN MEASUREMENTS AND RESULTS: The activity generated by 636 270 users with 2 876 394 appointments was studied. Mean frequency of attendance in the Gran Canaria Health Area was 4.52, with a 67.3% use rate. The user causing 11 or more visits per year was defined as an over-user. 13.4% of users were over-users and caused among them 52.3% of visits. 32.7% of users registered made no visit. CONCLUSIONS: A small section of the population causes over half the consultations. The characteristics of these users need to be analysed so that programmes can be worked out to decrease their frequency of use. The integrated management software for primary care enables this information to be analysed and serves as a support for the primary care teams. Special attention needs to be paid to the population that does not use the health centres.

Ambulatory Care Information Systems↗
PubMed2005

BrainTrain: brain simulator for medical VR application.

The brain is known as the most complex organ in the human body. Due to its complexity, learning and understanding the anatomy and functions of the cerebral cortex without effective learning assistance is rather difficult for medical novices and students in health and biological sciences. In this paper, we present a new virtual reality (VR) simulator for neurological education and neurosurgery. The system is based on a new three-dimensional (3D) user-computer interface design with a tangible object and a force-torque sensor. The system is combined with highly interactive computer-generated graphics and acoustics to provide multi-modal interactions through the user's sensory channels (vision, tactile, haptic and auditory). The system allows the user to feel the simulated object from its physical model that formed the interface device, while exploring or interacting with the mimicked computer-generated object in the virtual environment (VE). Unlike other passive interface devices, our system can detect the position and orientation of the interacting force in real-time, based on the system's set-up and a force-torque data acquisition technique. As long as the user is touching the model, the positions of the user's fingertip in the VE can be determined and is synchronized with the finger's motion in the physical world without requirement of an additional six-degree-of-freedom tracking device. The prior works have shown the use of the system set-up in medical applications. We demonstrate the system for neurological education and neurosurgery as a recent application. The main functions of the simulator contribute to education in neuroanatomy and visualization for diagnostic and pre-surgery planning. Once the user has touched the model, the system will mark the associated anatomy region and will provide the information of the region in terms of text note and/or sound. The user can switch from anatomy to the brain's function module, which will give details of motor, sensory or other cortical functions associated to the touch areas. In addition, the user can generate and visualize arbitrary cross-sectional images from corresponding to the magnetic resonance imaging (MRI) datasets either for training or for diagnostic purpose. The user can manipulate the cross-section image interactively and intuitively by moving the finger on the interface device.

Brain↗
PubMed2000

Lateral arm fascial flap: microarterial anatomy and potential clinical applications.

Previously, muscle flaps and the omentum have been used to indirectly vascularize tissues. Induction of synangiogenesis, or indirect vascularization through the formation of collateral vessels, occurs through the development of vascular connections at the interface between the donor and recipient tissues. Unfortunately, muscle and omental flaps are bulky and, when used to salvage ischemic hands and digits, may limit digital range of motion. Additionally, disadvantages to using omentum include a requirement for an intraabdominal procedure and a lack of subsequent donor tissue if the contralateral limb becomes involved at a later time. The purpose of this anatomic study was to develop a customized lateral arm fascial flap (LAFF) which may be used for flap prefabrication or synangiogenesis of non-bypassable ischemia. Detailed anatomic dissections were performed to more thoroughly define the microvascular anatomy of the LAFF. Computer analysis of the data was performed to demonstrate the potential clinical application of using the LAFF. Dissections revealed a consistent pattern of vessels branching within the lateral arm fascia and to the neighboring musculature. In order to optimize the surgical use of available tissue, computer-aided design techniques were used to model a reliable fascial free flap for inducing synangiogenesis while imparting minimal donor-site morbidity. Anatomic studies of the LAFF revealed pitfalls in flap dissection, while computer-generated models illustrated the detailed microarterial anatomy of the LAFF and potential limitations in flap design. Potential clinical applications for use of this low-profile fasciovascular conduit are noted.

Arm↗
PubMed1992

Computer-aided molecular modeling and design of DNA-inserting molecules.

Intercalators are molecules capable of sliding between base pairs without disturbing the overall stacking pattern. In addition, there may exist molecules capable of inserting into a base pair thereby disrupting the hydrogen bonds and replacing them with new hydrogen bonds. A molecule probably capable of inserting, i.e., an insertor, is the diketopiperazine cyclo-[Gly-Gly] (1). A barbiturate (2), alloxan (3), a pyrimidine derivative (4) and a hydantoin (5) were also studied as possible insertors. Furthermore, molecules such as ethyleneurea (6), succinimide (7), as well as a malonamide derivative (8) and oxamide derivatives (9-11) were studied in order to investigate the arrangement and the number of hydrogen bonds necessary for insertion. Molecules 12-14 were designed and studied for their capacity to act as bisinsertors and/or bisintercalators. These molecules feature two diketopiperazine moieties which are connected via a diphenyl(thio)ether, i.e., 12 and 13, or a bisphenol A spacer, i.e., 14. The latter molecule (14) seems a promising candidate as a bisinsertor.

Computers↗
PubMed2001

The beta-beta-alpha fold: explorations in sequence space.

The computational redesign of the second zinc finger of Zif268 to produce a 28 residue peptide (FSD-1) that assumes a betabetaalpha fold without metal binding was recently reported. In order to explore the tolerance of this metal-free fold towards sequence variability, six additional peptides resulting from the ORBIT computational protein design process were synthesized and characterized. The experimental stabilities of five of these peptides are strongly correlated with the energies calculated by ORBIT. However, when a peptide with a mutation in the beta-turn is examined, the calculated stability does not accurately predict the experimentally determined stability. The NMR solution structure of a peptide incorporating this mutation (FSD-EY) reveals that the register between the beta-strands is different from the model structure used to select and score the sequences. FSD-EY has a type I' turn instead of the target EbaaagbE turn (rubredoxin knuckle). Two additional peptides that have improved side-chain to backbone hydrogen bonding and turn propensity for the target turn were characterized. Both are of stability comparable to that of FSD-1. These results demonstrate the robustness of the ORBIT protein design methods and underscore the need for continued improvements in negative design.

Algorithms↗