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De novo designed transmembrane peptides activating the α5β1 integrin.
Mravic M, Hu H, Lu Z, Bennett JS, Sanders CR, Orr AW, DeGrado WF
(2018) Protein Eng Des Sel 31: 181-190
MeSH Terms: Amino Acid Sequence, Cell Membrane, Computer-Aided Design, Drug Design, Humans, Integrin alpha5beta1, Micelles, Peptides, Protein Conformation, alpha-Helical, Protein Domains
Show Abstract · Added November 21, 2018
Computationally designed transmembrane α-helical peptides (CHAMP) have been used to compete for helix-helix interactions within the membrane, enabling the ability to probe the activation of the integrins αIIbβ3 and αvβ3. Here, this method is extended towards the design of CHAMP peptides that inhibit the association of the α5β1 transmembrane (TM) domains, targeting the Ala-X3-Gly motif within α5. Our previous design algorithm was performed alongside a new workflow implemented within the widely used Rosetta molecular modeling suite. Peptides from each computational approach activated integrin α5β1 but not αVβ3 in human endothelial cells. Two CHAMP peptides were shown to directly associate with an α5 TM domain peptide in detergent micelles to a similar degree as a β1 TM peptide does. By solution-state nuclear magnetic resonance, one of these CHAMP peptides was shown to bind primarily the integrin β1 TM domain, which itself has a Gly-X3-Gly motif. The second peptide associated modestly with both α5 and β1 constructs, with slight preference for α5. Although the design goal was not fully realized, this work characterizes novel CHAMP peptides activating α5β1 that can serve as useful reagents for probing integrin biology.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Autocorrelation descriptor improvements for QSAR: 2DA_Sign and 3DA_Sign.
Sliwoski G, Mendenhall J, Meiler J
(2016) J Comput Aided Mol Des 30: 209-17
MeSH Terms: Computer-Aided Design, Drug Design, Drug Discovery, Humans, Models, Molecular, Neural Networks, Computer, Quantitative Structure-Activity Relationship
Show Abstract · Added February 5, 2016
Quantitative structure-activity relationship (QSAR) is a branch of computer aided drug discovery that relates chemical structures to biological activity. Two well established and related QSAR descriptors are two- and three-dimensional autocorrelation (2DA and 3DA). These descriptors encode the relative position of atoms or atom properties by calculating the separation between atom pairs in terms of number of bonds (2DA) or Euclidean distance (3DA). The sums of all values computed for a given small molecule are collected in a histogram. Atom properties can be added with a coefficient that is the product of atom properties for each pair. This procedure can lead to information loss when signed atom properties are considered such as partial charge. For example, the product of two positive charges is indistinguishable from the product of two equivalent negative charges. In this paper, we present variations of 2DA and 3DA called 2DA_Sign and 3DA_Sign that avoid information loss by splitting unique sign pairs into individual histograms. We evaluate these variations with models trained on nine datasets spanning a range of drug target classes. Both 2DA_Sign and 3DA_Sign significantly increase model performance across all datasets when compared with traditional 2DA and 3DA. Lastly, we find that limiting 3DA_Sign to maximum atom pair distances of 6 Å instead of 12 Å further increases model performance, suggesting that conformational flexibility may hinder performance with longer 3DA descriptors. Consistent with this finding, limiting the number of bonds in 2DA_Sign from 11 to 5 fails to improve performance.
1 Communities
2 Members
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7 MeSH Terms
Interrogating HIV integrase for compounds that bind--a SAMPL challenge.
Peat TS, Dolezal O, Newman J, Mobley D, Deadman JJ
(2014) J Comput Aided Mol Des 28: 347-62
MeSH Terms: Computer-Aided Design, Drug Design, HIV, HIV Infections, HIV Integrase, HIV Integrase Inhibitors, Humans, Models, Molecular, Protein Binding, Software
Show Abstract · Added March 20, 2014
Tremendous gains and novel methods are often developed when people are challenged to do something new or difficult. This process is enhanced when people compete against each other-this can be seen in sport as well as in science and technology (e.g. the space race). The SAMPL challenges, like the CASP challenges, aim to challenge modellers and software developers to develop new ways of looking at molecular interactions so the community as a whole can progress in the accurate prediction of these interactions. In order for this challenge to occur, data must be supplied so the prospective test can be done. We have supplied unpublished data related to a drug discovery program run several years ago on HIV integrase for the SAMPL4 challenge. This paper describes the methods used to obtain these data and the chemistry involved.
0 Communities
1 Members
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10 MeSH Terms
Computational methods in drug discovery.
Sliwoski G, Kothiwale S, Meiler J, Lowe EW
(2014) Pharmacol Rev 66: 334-95
MeSH Terms: Animals, Computer-Aided Design, Drug Discovery, Drug-Related Side Effects and Adverse Reactions, Humans, Ligands, Molecular Structure, Pharmaceutical Preparations, Pharmacokinetics
Show Abstract · Added January 24, 2015
Computer-aided drug discovery/design methods have played a major role in the development of therapeutically important small molecules for over three decades. These methods are broadly classified as either structure-based or ligand-based methods. Structure-based methods are in principle analogous to high-throughput screening in that both target and ligand structure information is imperative. Structure-based approaches include ligand docking, pharmacophore, and ligand design methods. The article discusses theory behind the most important methods and recent successful applications. Ligand-based methods use only ligand information for predicting activity depending on its similarity/dissimilarity to previously known active ligands. We review widely used ligand-based methods such as ligand-based pharmacophores, molecular descriptors, and quantitative structure-activity relationships. In addition, important tools such as target/ligand data bases, homology modeling, ligand fingerprint methods, etc., necessary for successful implementation of various computer-aided drug discovery/design methods in a drug discovery campaign are discussed. Finally, computational methods for toxicity prediction and optimization for favorable physiologic properties are discussed with successful examples from literature.
1 Communities
1 Members
0 Resources
9 MeSH Terms
A study on the theoretical and practical accuracy of conoscopic holography-based surface measurements: toward image registration in minimally invasive surgery.
Burgner J, Simpson AL, Fitzpatrick JM, Lathrop RA, Herrell SD, Miga MI, Webster RJ
(2013) Int J Med Robot 9: 190-203
MeSH Terms: Computer-Aided Design, Equipment Design, Equipment Failure Analysis, Holography, Imaging, Three-Dimensional, Laparoscopy, Lasers, Minimally Invasive Surgical Procedures, Reproducibility of Results, Robotics, Sensitivity and Specificity, Subtraction Technique, Surgery, Computer-Assisted
Show Abstract · Added May 27, 2014
BACKGROUND - Registered medical images can assist with surgical navigation and enable image-guided therapy delivery. In soft tissues, surface-based registration is often used and can be facilitated by laser surface scanning. Tracked conoscopic holography (which provides distance measurements) has been recently proposed as a minimally invasive way to obtain surface scans. Moving this technique from concept to clinical use requires a rigorous accuracy evaluation, which is the purpose of our paper.
METHODS - We adapt recent non-homogeneous and anisotropic point-based registration results to provide a theoretical framework for predicting the accuracy of tracked distance measurement systems. Experiments are conducted a complex objects of defined geometry, an anthropomorphic kidney phantom and a human cadaver kidney.
RESULTS - Experiments agree with model predictions, producing point RMS errors consistently < 1 mm, surface-based registration with mean closest point error < 1 mm in the phantom and a RMS target registration error of 0.8 mm in the human cadaver kidney.
CONCLUSIONS - Tracked conoscopic holography is clinically viable; it enables minimally invasive surface scan accuracy comparable to current clinical methods that require open surgery.
Copyright © 2012 John Wiley & Sons, Ltd.
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1 Members
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13 MeSH Terms
Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project.
Pulley JM, Denny JC, Peterson JF, Bernard GR, Vnencak-Jones CL, Ramirez AH, Delaney JT, Bowton E, Brothers K, Johnson K, Crawford DC, Schildcrout J, Masys DR, Dilks HH, Wilke RA, Clayton EW, Shultz E, Laposata M, McPherson J, Jirjis JN, Roden DM
(2012) Clin Pharmacol Ther 92: 87-95
MeSH Terms: Aryl Hydrocarbon Hydroxylases, Cardiac Catheterization, Clopidogrel, Computer-Aided Design, Cytochrome P-450 CYP2C19, Decision Support Systems, Clinical, Genetic Variation, Genotyping Techniques, Humans, Patient Selection, Pharmacogenetics, Platelet Aggregation Inhibitors, Precision Medicine, Ticlopidine
Show Abstract · Added December 10, 2013
The promise of "personalized medicine" guided by an understanding of each individual's genome has been fostered by increasingly powerful and economical methods to acquire clinically relevant information. We describe the operational implementation of prospective genotyping linked to an advanced clinical decision-support system to guide individualized health care in a large academic health center. This approach to personalized medicine entails engagement between patient and health-care provider, identification of relevant genetic variations for implementation, assay reliability, point-of-care decision support, and necessary institutional investments. In one year, approximately 3,000 patients, most of whom were scheduled for cardiac catheterization, were genotyped on a multiplexed platform that included genotyping for CYP2C19 variants that modulate response to the widely used antiplatelet drug clopidogrel. These data are deposited into the electronic medical record (EMR), and point-of-care decision support is deployed when clopidogrel is prescribed for those with variant genotypes. The establishment of programs such as this is a first step toward implementing and evaluating strategies for personalized medicine.
0 Communities
6 Members
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14 MeSH Terms
Potential of discrete Gaussian edge feathering method for improving abutment dosimetry in eMLC-delivered segmented-field electron conformal therapy.
Eley JG, Hogstrom KR, Matthews KL, Parker BC, Price MJ
(2011) Med Phys 38: 6610-22
MeSH Terms: Algorithms, Cluster Analysis, Computer-Aided Design, Electrons, Equipment Design, Equipment Failure Analysis, Feasibility Studies, Learning, Normal Distribution, Radiometry, Radiotherapy, Conformal, Reproducibility of Results, Sensitivity and Specificity
Show Abstract · Added March 30, 2020
PURPOSE - The purpose of this work was to investigate the potential of discrete Gaussian edge feathering of the higher energy electron fields for improving abutment dosimetry in the planning volume when using an electron multileaf collimator (eMLC) to deliver segmented-field electron conformal therapy (ECT).
METHODS - A discrete (five-step) Gaussian edge spread function was used to match dose penumbras of differing beam energies (6-20 MeV) at a specified depth in a water phantom. Software was developed to define the leaf eMLC positions of an eMLC that most closely fit each electron field shape. The effect of 1D edge feathering of the higher energy field on dose homogeneity was computed and measured for segmented-field ECT treatment plans for three 2D PTVs in a water phantom, i.e., depth from the water surface to the distal PTV surface varied as a function of the x-axis (parallel to leaf motion) and remained constant along the y-axis (perpendicular to leaf motion). Additionally, the effect of 2D edge feathering was computed and measured for one radially symmetric, 3D PTV in a water phantom, i.e., depth from the water surface to the distal PTV surface varied as a function of both axes. For the 3D PTV, the feathering scheme was evaluated for 0.1-1.0-cm leaf widths. Dose calculations were performed using the pencil beam dose algorithm in the Pinnacle(3) treatment planning system. Dose verification measurements were made using a prototype eMLC (1-cm leaf width).
RESULTS - 1D discrete Gaussian edge feathering reduced the standard deviation of dose in the 2D PTVs by 34, 34, and 39%. In the 3D PTV, the broad leaf width (1 cm) of the eMLC hindered the 2D application of the feathering solution to the 3D PTV, and the standard deviation of dose increased by 10%. However, 2D discrete Gaussian edge feathering with simulated eMLC leaf widths of 0.1-0.5 cm reduced the standard deviation of dose in the 3D PTV by 33-28%, respectively.
CONCLUSIONS - A five-step discrete Gaussian edge spread function applied in 2D improves the abutment dosimetry but requires an eMLC leaf resolution better than 1 cm.
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1 Members
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MeSH Terms
Integrated system for combined Raman spectroscopy-spectral domain optical coherence tomography.
Patil CA, Kalkman J, Faber DJ, Nyman JS, van Leeuwen TG, Mahadevan-Jansen A
(2011) J Biomed Opt 16: 011007
MeSH Terms: Animals, Computer-Aided Design, Equipment Design, Equipment Failure Analysis, Lighting, Mice, Reproducibility of Results, Sensitivity and Specificity, Spectrum Analysis, Raman, Systems Integration, Tomography, Optical Coherence
Show Abstract · Added March 24, 2014
Raman spectroscopy (RS) and optical coherence tomography (OCT) are powerful tools for optical analysis of tissues with mutually complementary strengths and limitations. OCT excels at visualizing tissue microstructure but lacks molecular specificity, while RS can relay tissue biochemical composition but typically cannot relate microstructure. Previous implementations of combined RS-OCT have utilized a common sample arm while maintaining independent RS and OCT detection arms. We present the design and application of an integrated RS-OCT instrument with a common detection arm for both RS and OCT. The detector is a spectrograph capable of sequential detection of the 855-nm OCT signal and the Raman scatter generated by a 785-nm source. The capabilities of the instrument are demonstrated ex vivo in the calvaria and retina of rodents, as well as in vivo in human skin.
0 Communities
1 Members
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11 MeSH Terms
Practical considerations for the design of sparse-spokes pulses.
Jankiewicz M, Zeng H, Moore JE, Anderson AW, Avison MJ, Welch EB, Gore JC
(2010) J Magn Reson 203: 294-304
MeSH Terms: Brain, Computer-Aided Design, Equipment Design, Equipment Failure Analysis, Humans, Image Enhancement, Magnetic Resonance Imaging, Reproducibility of Results, Sensitivity and Specificity, Signal Processing, Computer-Assisted
Show Abstract · Added May 29, 2013
Sparse-spokes pulses are 2D slice-selective pulses that effectively mitigate inhomogeneities in the transmitted RF field and reduce unwanted RF artifacts in MR images. Here we consider the practical design of such pulses for high-field MRI and demonstrate limitations of the technique. We analyze the performance of pulses considering input noise as well as other effects such as saturation and T2( *) relaxation. We discuss in detail the correspondence between the reduction of RF inhomogeneities and the fidelity of the input parameters, such as the transmit B1+ field map and combined phase of the main B0 field and eddy-currents. Results include simulations, utilizing 7 T field maps acquired in phantoms and in-vivo, as well as in-vivo experiments. The necessary performance of system hardware components to achieve significant improvements is described.
2010 Elsevier Inc. All rights reserved.
0 Communities
3 Members
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10 MeSH Terms
Design parameters and sensitivity analysis of polymer-cladded porous silicon waveguides for small molecule detection.
Jiao Y, Weiss SM
(2010) Biosens Bioelectron 25: 1535-8
MeSH Terms: Biopolymers, Biosensing Techniques, Computer-Aided Design, Equipment Design, Equipment Failure Analysis, Molecular Weight, Polymers, Porosity, Refractometry, Reproducibility of Results, Sensitivity and Specificity, Silicon
Show Abstract · Added April 27, 2017
The relationship between the design parameters and small molecule detection sensitivity of porous silicon waveguides is theoretically and experimentally analyzed. Perturbation theory calculations suggest that the sensitivity asymptotically approaches infinity as the porosity of the waveguide approaches a critical porosity for a given mode and the resonant coupling angle of light into the waveguide approaches 90 degrees. Experimental measurements confirm the trend of the porosity-dependent sensitivity for multiple waveguide modes. Given the limitations of the available measurement apparatus that restricts the maximum coupling angle to 68 degrees, a high sensitivity of 120 degrees/RIU was demonstrated for the detection of 0.8 nm molecules attached inside a polymer-cladded nanoscale porous silicon waveguide. Optimized porous dielectric waveguides enable enhanced small molecule detection sensitivity due to their large available surface area for molecular binding.
Copyright 2009 Elsevier B.V. All rights reserved.
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12 MeSH Terms