39 research outputs found
PLHINT: A knowledge-driven computational approach based on the intermolecular H bond interactions at the protein-ligand interface from docking solutions
No full textThe tendency of docking scoring functions to generate crystal close conformations of ligands bound to protein structures face limitations in not reproducing the exact crystal intermolecular contacts in dock poses. Intermolecular H bond contacts enumerated at the protein-docked ligand interface can be used to train scoring models and improve virtual screening performance. There is a need to incorporate additional knowledge of protein-ligand H bond contacts in extension to crystal contacts from docking solutions within the reproducibility efficiency of the docking program. A computational approach PLHINT (Protein-ligand H bond interaction pattern) is presented here which extracts intermolecular H bond interactions from native-like docked ligand poses, transform into the scoring scheme and apply over the virtual screening results of database molecules. The basic premise of the PLHINT approach is to score the most observed H bond patterns with the high score to achieve high recovery rates. Tested on ten diverse DUD-E benchmark datasets, the approach has demonstrated better overall performance and ligand enrichment competency over virtual screening results generated by three genetic algorithm-based docking programs viz. AutoDock Vina, FIexAID and PLANTS. Furthermore, the approach has successfully recovered the poor and random virtual screening results with better enrichments. (C) 2017 Elsevier Inc. All rights reserved
Receptor pharmacophore ensemble (REPHARMBLE): a probabilistic pharmacophore modeling approach using multiple protein-ligand complexes
No full textEnsemble methods are gaining more importance in structure-based approaches as single protein-ligand complexes strongly influence the outcomes of virtual screening. Structure-based pharmacophore modeling based on a single protein-ligand complex with complex feature combinations is often limited to certain chemical classes. The REPHARMBLE (receptor pharmacophore ensemble) approach presented here examines the ability of an ensemble of selected protein-ligand complexes to populate pharmacophore space in the ligand binding site, rigorously assesses the importance of pharmacophore features using Poisson statistic and information theory-based entropy calculations, and generates pharmacophore models with high probabilities. In addition, an ensemble scoring function that combines all the resultant high-scoring pharmacophore models to score molecules is derived. The REPHARMBLE approach was evaluated on ten DUD-E benchmark datasets and afforded good screening performance, as measured by receiver operating characteristic, enrichment factor and Guner-Henry score. Although one of the high-scoring models achieved superior statistical results in each dataset, the ensemble scoring function balanced the shortcomings of each model and passed with close performance measures. This approach offers a reliable way of choosing the best-scoring features to build four-feature pharmacophore queries and customize a target-biased pharmacophore ensemble' scoring function for subsequent virtual screening
Multi-Pharmacophore Modeling of Caspase-3 Inhibitors using Crystal, Dock and Flexible Conformation Schemes
No full text
Aim and Objective:
Numerous caspase-3 drug discovery projects were found to have relied
on single receptor as the template to recognize most promising small molecule candidates using
docking approach. Alternatively, some researchers were contingent upon ligand-based alignment to
build up an empirical relationship between ligand functional groups and caspase-3 inhibitory activity
quantitatively. To connect both caspase-3 receptor details and its inhibitors chemical functionalities, this
study was undertaken to develop receptor- and ligand-pharmacophore models based on different
conformational schemes.
Material and Methods:
A multi-pharmacophore modeling strategy is carried out based on three
conformational schemes of pharmacophore hypothesis generation to screen caspase-3 inhibitors from
database. The schemes include (i) flexible (conformations unrestricted or flexible during
pharmacophore mapping), (ii) dock (conformations obtained using FlexX docking method) and (iii)
crystal (extracted from multiple caspase-3-ligand complexes from PDB repository) conformations of
query ligands. The pharmacophore models developed using these conformational schemes were then
used to identify probable caspase-3 inhibitors from ZINC database.
Results:
We noticed better sensitivity with good specificity measures returned by candidate
pharmacophore hypotheses across each conformation type and recognized crucial pharmacophore
features that enable caspase-3 binding. Pharmacophore modeling based on flexible conformational
scheme indicated that the crystal structure 3KJF (AAAADH) is the best receptor structure to perform
receptor-based pharmacophore screening of caspase-3 inhibitors. When multiple crystal structures were
included, the hypothesis (HAAA) is more generalized. Superimposition of multiple co-crystal ligands
from various caspase-3 PDB entries in crystallographic binding mode revealed similar hypothesis
(HAAA). Further, FlexX-guided dock conformations of validation dataset showed that the crystal
structure 1RE1 is the best-suited for dock-based pharmacophore models. Database screening using
these pharmacophore hypotheses identified N'-[6-(benzimidazol-1-yl)-5-nitro-pyrimidin-4-yl]-4
methylbenzenesulfonohydrazide and 2-nitro-N'-[5-nitro-6-[N'-(p-tolylsulfonyl)hydrazino]pyrimidin-4-
yl]benzohydrazide as the probable caspase-3 inhibitors.
Conclusion:
N'-[6-(benzimidazol-1-yl)-5-nitro-pyrimidin-4-yl]-4 methylbenzenesulfonohydrazide and
2-nitro-N'-[5-nitro-6-[N'-(p-tolylsulfonyl)hydrazino]pyrimidin-4-yl]benzohydrazide may be tested for
caspase-3 inhibition. We believe that potential caspase-3 inhibitors can be recognized efficiently by
adapting multi-pharmacophore models in database screening.
</jats:sec
Innate sensing pathways: Defining new innate immune and inflammatory cell death pathways has shaped translational applications.
No full textThe past 20 years of research has elucidated new innate immune sensing and cell death pathways with disease relevance. Future molecular characterization of these pathways and their crosstalk and functional redundancies will aid in development of therapeutic strategies
Exploration of interaction zones of β-tubulin colchicine binding domain of helminths and binding mechanism of anthelmintics
No full textSystems pathology: a bottom-up approach for understanding fibroblast-epithelial interactions in breast cancer
No full textBreast cancer is prevalent both in the United States and worldwide. While both screening tests and targeted therapies are available, there are still challenges in the diagnosis, prognosis, and treatment of breast cancer. We were motivated to develop a new approach for both studying the etiology of heterogeneity in breast cancer phenotypes and predicting the course of disease in tumor biopsies using an emerging chemical imaging technology.
It has been described extensively that the tumor microenvironment, or stroma, can promote or suppress cancer phenotypes in many tissues. We hypothesized that interaction with fibroblasts, the predominant cell type found in the breast tumor stroma, is a critical regulatory step in the progression of breast cancer from confined to invasive disease. Hence, we developed a novel three-dimensional co-culture model to investigate this interaction. The development and validation of this model is described in chapter two. We used it first to determine how cancerous molecular signatures can propagate from cancerous to normal epithelium through the activation of fibroblasts. Changes in the architectural morphology of normal mammary acini were used as a metric to determine cancer progression, in addition to gene expression analysis and cell-based assays such as proliferation and migration assays. This system is a robust and easily applied tool for investigating fibroblast-epithelial communication in a physiologically-relevant context.
The 3D co-culture system was used to investigate how fibroblasts impact the growth of estrogen receptor-positive (ER+) breast cancer cells and this is described in chapter three. ER+ is the most common subtype of breast cancer (>75%) and while these patients are eligible to receive targeted endocrine therapies, up to 30% of patients will experience a recurrence. Others will fail to respond to front-line endocrine therapies, while more patients will become resistant to endocrine therapies over time. We aimed to understand how fibroblasts play a role in the progression from hormone-dependent to hormone-independent growth. The cell culture data was translated to patient samples using bioinformatics approaches and label-free chemical imaging. Further, we define one aspect of the interaction between breast cancer cells and fibroblasts through identifying secreted proteins that are involved in the stromal-epithelial communication. The 43-protein signature can be used to classify breast cancer patients based on their corresponding gene expression profile, and we found that the signature is significantly upregulated in patients with more invasive disease.
In order to continue translating our results from cell culture to patient samples, we describe the application of label-free Fourier transform infrared spectroscopic imaging to monitoring breast cancer cell phenotypes. Chapter four details how biological changes can be spatially resolved in heterogeneous samples while in chapter five an approach to determine estrogen receptor presence and function in cell culture samples and patient biopsies is discussed. We show how FT-IR imaging can be used to define label-free spectroscopic signatures that are consistent between cell culture and patients, and explore how this approach may be used in the future to add additional information to current pathology practice.
We have developed a method to both understand the molecular mechanisms involved in how the microenvironment regulates early breast cancer phenotypes and to detect altered cellular phenotypes using label-free FT-IR imaging. We aim to apply this systems pathology approach to the development of novel diagnostic and prognostic signatures for determining the trajectory of cancer progression at very early stages.Item withdrawn by Mark Zulauf ([email protected]) on 2013-08-28T15:22:12Z
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University of Illinois Theses & Dissertations (ID: 1)
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Biped dynamic walker modeling and control for underactuated gait cycle
No full textA biped dynamic walker with two legs and two feet capable of walking in double support phase and allowing starting the gait cycle from rest position is proposed. The walker is actuated at the ankle joints alone with no hip actuator, fully actuated in double support phase, and unactuated in single support phase. Assuming a static configuration at the start of each single support phase, fixed point information for the gait cycle at various step lengths is extracted and represented with four parameters of a cubic polynomial. This is used as the end configuration for the position controller’s reference target in the double support phase. Actuation at the ankles considers the unilateral constraints at the front and rear feet. Even with trajectory tracking controller, low cost of transport is achieved by ensuring no negative power inputs during actuation. A proportional feedback controller is employed for cycle convergence, and the stability of gait cycles, disturbance handling, and energetic efficiency for various step lengths is shown through simulations. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature
Preparation and properties of bioactive coralline hydroxyapatite/fluoroapatite-zirconia composites
No full textProtein folding in living cells and under pressure
No full textProtein folding, the process through which proteins gain their functional structure, can be approached from the perspective of many disciplines. Starting with biology, we can probe how protein structure relates to function and consider how the fold of a protein interacts with the biological environment. From the chemical perspective, we can treat protein folding as a chemical reaction and study the thermodynamics and kinetics of the structural transition. With physics, we can understand the underlying forces that give rise to protein folding and use theory and simulation to describe the protein folding process on an atomic level. This thesis studies protein folding through the lens of all three of these fields with two interdisciplinary methodological themes: one at the interface of chemistry and physics and the other at the interface of biology and chemistry.
In section 1, we study in detail the kinetics of fast-folding reactions following pressure-jump perturbation and pair experiment with molecular dynamics simulations. The first chapter is a review of the effects of pressure on the structure of biomolecules as well as a brief literature review of pressure-probed protein folding kinetics. We see that the methodology to study pressure-jumps is generally limited by time-scale—very fast folding is hard to study by pressure—and chapter two presents an overview of a fast pressure-jump instrument that meets this challenge. Although this instrument was developed by the previous generation of graduate students, several significant improvements are summarized in the chapter with a detailed user manual for the instrumentation. Closing up the section, we use the fast pressure-jump instrumentation as well as temperature-jump instrumentation to study the microsecond pressure and temperature-jump refolding kinetics of the engineered WW domain FiP35, a model system for beta sheet folding. With a full complement of molecular dynamics experiments mimicking experimental conditions, we show that simulation and experiment are consistent with a four-state kinetic mechanism and highlight FiP35’s position at the boundary where activated intermediates and downhill folding meet.
Section 2 focuses on the interface of biology and chemistry, where we study how the protein folding reaction is impacted by immersion in the crowded intracellular environment and explore whether perturbations to the intracellular folding landscape can be linked to protein function. A review of the forces at play in the intracellular environment and the role that ultra-weak “quinary” interactions play inside living cells is presented in chapter 4, which also includes a review of the most recent literature studying biomolecular dynamics in their native environments. In chapter 5 we study the time-dependence of protein folding inside living cells as probed by live-cell fluorescent microscopy. We find that both the rate of folding and the thermodynamic stability of yeast phosphoglycerate kinase (PGK-FRET) are cell cycle-dependent, a process strictly regulated in time, suggesting that the interplay between the intracellular environment and proteins may impact their function. In chapter 6, a new probe to study protein folding in the cell is explored, namely the GFP/ReAsH Forster resonance energy transfer (FRET) pair. We show that this FRET pair suffers from bleaching artifacts but that directly excited ReAsH is an appealing prospect for studying protein folding in living cells on fast and slow time-scales. Finally, chapter 7 builds on the work presented in chapter 5 and chapter 6 by seeking a protein candidate whose function and in cell folding dynamics are linked. Several constructs of p53, a transcription factor, are explored as potential candidates for answering the question of whether protein activity level indeed can correlate with stability in living cells.Submission published under a 24 month embargo labeled 'U of I only', the embargo will last until 2017-08-01The student, Anna Wirth, accepted the attached license on 2015-06-23 at 10:44.The student, Anna Wirth, submitted this Dissertation for approval on 2015-06-23 at 10:58.This Dissertation was approved for publication on 2015-06-26 at 16:32.DSpace SAF Submission Ingestion Package generated from Vireo submission #8303 on 2015-09-29 at 14:58:36Made available in DSpace on 2015-09-29T20:49:33Z (GMT). No. of bitstreams: 2
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Harvesting Roadway Solar Energy-Performance of the Installed Infrastructure Integrated PV Bike Path
No full textSolar road technology provides an opportunity to harvest the vast, albeit dispersed, photovoltaic (PV) energy, while maximizing the land utilization. Deriving experience from the pioneering 70-m solar bike path installed in the Netherlands, this paper highlights the operational challenges and performance parameters using the first-year measured data. The theoretically predicted energy yield is compared with the measured energy yield. Based on the best performing module, the benchmark annual energy yield is set to 85&#x2013;90&#x00A0;kWh/m<formula><tex></tex></formula> specific to the installation site. It is shown that this value can be bettered by about 1.5 times if different cell technology such as monocrystalline is used. With different installation sites around the world, thermal behavior as well as annual energy yield changes. Theoretical proof is offered that it is not unreasonable to expect an annual energy yield in the upwards of 150&#x00A0;kWh/m<formula><tex></tex></formula> with solar road energy harvesting technology. For example, the annual yield is found to be 213&#x00A0;kWh/m<formula><tex></tex></formula> if the same model is simulated for a solar road PV installation in India, which increased further with the use of monocrystalline to almost 300&#x00A0;kWh/m<formula><tex></tex></formula>.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.DC systems, Energy conversion & StoragePhotovoltaic Materials and DevicesElectrical Sustainable Energ
