Computational Studies of Protein Dynamics and Drug Resistance PDF Download
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Author: Hani Mohammedali
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Author: Hani Mohammedali
Publisher:
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Category :
Languages : en
Pages : 0
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Author: Nir Ben-Tal
Publisher: Frontiers Media SA
ISBN: 2889742121
Category : Science
Languages : en
Pages : 139
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Author: Alessandro Grottesi
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Author: Marton Munz
Publisher:
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Category :
Languages : en
Pages :
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Author: Ilan Samish
Publisher: Humana
ISBN: 9781493966356
Category : Science
Languages : en
Pages : 0
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The aim this volume is to present the methods, challenges, software, and applications of this widespread and yet still evolving and maturing field. Computational Protein Design, the first book with this title, guides readers through computational protein design approaches, software and tailored solutions to specific case-study targets. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and cutting-edge, Computational Protein Design aims to ensure successful results in the further study of this vital field.
Author: Defang Ouyang
Publisher: John Wiley & Sons
ISBN: 1118573994
Category : Science
Languages : en
Pages : 350
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Book Description
Molecular modeling techniques have been widely used in drug discovery fields for rational drug design and compound screening. Now these techniques are used to model or mimic the behavior of molecules, and help us study formulation at the molecular level. Computational pharmaceutics enables us to understand the mechanism of drug delivery, and to develop new drug delivery systems. The book discusses the modeling of different drug delivery systems, including cyclodextrins, solid dispersions, polymorphism prediction, dendrimer-based delivery systems, surfactant-based micelle, polymeric drug delivery systems, liposome, protein/peptide formulations, non-viral gene delivery systems, drug-protein binding, silica nanoparticles, carbon nanotube-based drug delivery systems, diamond nanoparticles and layered double hydroxides (LDHs) drug delivery systems. Although there are a number of existing books about rational drug design with molecular modeling techniques, these techniques still look mysterious and daunting for pharmaceutical scientists. This book fills the gap between pharmaceutics and molecular modeling, and presents a systematic and overall introduction to computational pharmaceutics. It covers all introductory, advanced and specialist levels. It provides a totally different perspective to pharmaceutical scientists, and will greatly facilitate the development of pharmaceutics. It also helps computational chemists to look for the important questions in the drug delivery field. This book is included in the Advances in Pharmaceutical Technology book series.
Author: Jennifer E. Murzycki
Publisher:
ISBN:
Category :
Languages : en
Pages : 382
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Author: Benjamin Michael Samudio
Publisher:
ISBN: 9781369201079
Category :
Languages : en
Pages :
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Proteins are fascinating biomolecular "machines" that enable the chemistry of life to occur. They underlie such diverse processes as energy transduction and immunity. Science continuous to unravel how these proteins work and many exciting questions remain to be answered. A paramount goal in the study of proteins is the understanding of how protein structure and dynamics facilitate chemistry. Proteins undergo conformational changes which make certain chemistry more probable. Elucidating these conformational changes is a major challenge to which both experimental and computational methods are applied. Computational methods can complement experimental ones by modeling protein conformational changes at an atomic level of detail. In addition, more elaborate computational methods can model chemical changes and reactions. This provides a link between structure and chemistry which is central to descriptions of protein function. This dissertation describes my research involving proteins which has been carried out at two institutions, the University of California in Davis (UC Davis) and the Novartis Institutes for Biomedical Research (NIBR), and correspondingly is divided into two parts. Part I: Unidirectional Proton Translocation Involving Glu-242 of Cytochrome c Oxidase (UC Davis) Cytochrome c oxidase (CcO) is the fourth protein complex in the electron transport chain (ETC) of mitochondria and some bacteria. This protein is embedded within the proton impermeable inner membrane of mitochondria and outer membrane in bacteria. CcO functions to: 1) reduce dioxygen to water and 2) move protons in a scalar manner from a lower concentration of protons in the mitochondrial matrix to a higher concentration of protons in the intermembrane space in a process known as proton pumping. Proton pumping establishes an electrochemical gradient across the inner membrane which is essential to aerobic life. CcO is remarkable because it is able to pump protons against the electrochemical gradient via a thermodynamically unfavorable but unidirectional and productive trajectory. CcO is unique as of this writing, in that it is designated as a "true" proton pump meaning that the protons which are pumped through CcO are not also substrates in the redox reactions which occur within this enzyme. Though a wealth of knowledge has been generated regarding CcO, much uncertainty remains about the microscopic details of the proton pumping process. Experimental methods have produced a detailed framework describing many aspects of CcO structure and function, however, probing this enzyme at the molecular level can be difficult. To this end, computational molecular modeling offers a complement to experimental efforts. The methods that are a part of computational molecular modeling can provide keen insight into biophysical processes. There are many different methods and ways to apply them, however, and it is not always straightforward how to best develop and deploy a model for a particular system. CcO presents an especially challenging system since the process of proton translocation involves levels of detail spanning electronic structure dynamics to large protein conformational changes. Computational methods must therefore be systematically tested and validated in order to increase confidence that their results are meaningful for investigations of CcO. In the current work, several computational models of CcO are compared. These models differ from one another in the level of detail describing a key region of the proton pumping pathway within CcO. This region contains a highly conserved residue, Glu-242 (bovine heart mitochondria numbering), which has been shown to be pivotal in relaying protons across the proton pumping pathway. The results of this work indicate that there are differences regarding the energetics and dynamics of Glu-242 side chain isomerization depending on the level of detail used in the model. These differences lead to differing descriptions of proton translocation as it involves Glu-242 and underscores the need to thoroughly examine the application of computational models. In Chapter 1, the major structures and functioning of CcO is outlined. The analogy that underlies this chapter is of CcO functioning similar to a macroscopic pump in moving protons from one side of the membrane to the other. The CcO reaction cycle is akin to the repetitive motions of a piston as it operates to pump material. In Chapter 2, the proton pump pathway through CcO is characterized. The focus then collects on a region of this pathway which is instrumental in the process of proton pumping named the "motif" region. Finally a four-state model is used to describe the participation in proton pumping of Glu-242 or its physiochemical analogue at this region. In Chapter 3, proton leaks and proton leak prevention are described. Proton leaks are thought to occur in some structural variants of CcO. In these cases, the unidirectional and productive movement of protons through CcO is compromised as indicated by abnormal proton pumping stoichiometry. Kinetic gating is a conceptual framework whereby the prevention of these leaks may be rationalized. This chapter ends with the description of a criterion that must be met in order to prevent protons from leaking. Chapter 4 introduces common methods used in molecular modeling. Finally, in Chapter 5 computational molecular models involving the motif region are compared. These models employ varying levels of detail. This offers a test of how increasing levels of model detail effects the conclusions which might be drawn regarding proton pumping. A proposal for how unidirectional proton translocation may occur in CcO is offered based on the results of the molecular models at the higher level of detail. In conclusion, these models are used to speculate on how proton leaks occur in structural variants of CcO and how unidirectional proton translocation may occur in CcO enzymes which lack Glu-242 or its equivalent. Part II: Ensemble Surrogate AutoShim: Probing Sensitivity to Parameter Modification (NIBR) Ensemble Surrogate AutoShim (ESA) is a powerful and versatile virtual docking and screening method which has proven to be useful in drug discovery and design. ESA is powerful in that it transforms general all-purpose scoring functions into target-tailored scoring functions using a combined 2D and 3D-QSAR based approach that involves virtual docking. These target-tailored scoring functions are then trained to reproduce bioactivity data against a given target resulting in a knowledge-based model that is used in virtual screening. Held-out test set validations of ESA models show that they routinely outperforms exclusively all-purpose scoring function based approaches. Chapter 1 outlines the ESA method in general. The versatility of the ESA method stems from the fact that various ligand preparation, docking and scoring, and pose filtering and refinement schemes may be implemented within the ESA framework. For example, the ESA method is open to the inclusion of any conventional all-purpose scoring function and docking program within its framework. This versatility offers flexibility in the implementation of the ESA method and invites an exploration of the parameters underlying this method. In Chapter 2, a systematic evaluation of ESA parameter modification is undertaken and quantified through statistical analysis. The results of this work indicate that several parameters significantly influence the quality of ESA models. Based on these results, a protocol is proposed which produces the most predictive ESA models on average of any parameter configuration and protocol studied so far on the data set evaluated.
Author: Anil Kumar Saxena
Publisher: Springer Nature
ISBN: 3030852814
Category : Science
Languages : en
Pages : 405
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Book Description
This book reviews recent physicochemical and biophysical techniques applied in drug discovery research, and it outlines the latest advances in computational drug design. Divided into 10 chapters, the book discusses about the role of structural biology in drug discovery, and offers useful application cases of several biophysical and computational methods, including time-resolved fluorometry (TRF) with Förster resonance energy transfer (FRET), X-Ray crystallography, nuclear magnetic resonance spectroscopy, mass spectroscopy, generative machine learning for inverse molecular design, quantum mechanics/molecular mechanics (QM/MM,ONIOM) and quantum molecular dynamics (QMT) methods. Particular attention is given to computational search techniques applied to peptide vaccines using novel mathematical descriptors and structure and ligand-based virtual screening techniques in drug discovery research. Given its scope, the book is a valuable resource for students, researchers and professionals from pharmaceutical industry interested in drug design and discovery.
Author: Marco Tutone
Publisher:
ISBN: 9783036527789
Category :
Languages : en
Pages : 387
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Book Description
This book is a collection of original research articles in the field of computer-aided drug design. It reports the use of current and validated computational approaches applied to drug discovery as well as the development of new computational tools to identify new and more potent drugs.
