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Author: Kira A. Armacost
Publisher:
ISBN: 9780841298057
Category : Drug development
Languages : en
Pages :
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Book Description
"This book is about Free Energy Methods in Drug Discovery: Current State and Future Directions"--
Author: Kira A. Armacost
Publisher:
ISBN: 9780841298057
Category : Drug development
Languages : en
Pages :
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Book Description
"This book is about Free Energy Methods in Drug Discovery: Current State and Future Directions"--
Author: M. Rami Reddy
Publisher: Springer Science & Business Media
ISBN: 9780306466762
Category : Medical
Languages : en
Pages : 420
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Book Description
Free energy calculations represent the most accurate computational method available for predicting enzyme inhibitor binding affinities. Advances in computer power in the 1990s enabled the practical application of these calculations in rationale drug design. This book represents the first comprehensive review of this growing area of research and covers the basic theory underlying the method, numerous state of the art strategies designed to improve throughput and dozen examples wherein free energy calculations were used to design and evaluate potential drug candidates.
Author: Christophe Chipot
Publisher: Springer Science & Business Media
ISBN: 3540384472
Category : Language Arts & Disciplines
Languages : en
Pages : 528
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Book Description
Free energy constitutes the most important thermodynamic quantity to understand how chemical species recognize each other, associate or react. Examples of problems in which knowledge of the underlying free energy behaviour is required, include conformational equilibria and molecular association, partitioning between immiscible liquids, receptor-drug interaction, protein-protein and protein-DNA association, and protein stability. This volume sets out to present a coherent and comprehensive account of the concepts that underlie different approaches devised for the determination of free energies. The reader will gain the necessary insight into the theoretical and computational foundations of the subject and will be presented with relevant applications from molecular-level modelling and simulations of chemical and biological systems. Both formally accurate and approximate methods are covered using both classical and quantum mechanical descriptions. A central theme of the book is that the wide variety of free energy calculation techniques available today can be understood as different implementations of a few basic principles. The book is aimed at a broad readership of graduate students and researchers having a background in chemistry, physics, engineering and physical biology.
Author: Lin Song
Publisher:
ISBN: 9781083282941
Category : Electronic dissertations
Languages : en
Pages : 169
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Book Description
With the increasing power of computers, computational studies have become more and more significant in drug discovery. High binding free energy is one of the major requirements for an effective drug molecule, hence much effort has been spent to develop fast and accurate computational free energy methods. In this thesis, different free energy methods, i.e. umbrella sampling, thermodynamic integration, and double decoupling method, are applied to different systems related to drug discovery. For the first study, umbrella sampling studies are performed to calculate the absolute binding free energies of host-guest systems which serve as great model systems to assess free energy methods due to the small size of the systems, etc. We find that benchmarking our method with known systems can significantly improve the results for the unknown systems: the overall RMSE of the binding free energy versus experiment is reduced from 5.59 kcal/mol to 2.36 kcal/mol. The source of error could be from the un-optimized force constants used in umbrella sampling (hence possibly poor window overlaps), as well as force field, sampling issues, etc. Our results ranked 4th best in the Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL6) blind challenge. For the second study, GPU accelerated thermodynamic integration (GPU-TI) is used to compute the relative binding free energies of a protein-ligand dataset originally assembled by Schrodinger, Inc. The calculations of relative binding free energies between different ligands are the typical process in the lead optimization of computer-aided drug discovery. In our study using GPU-TI from AMBER 18 with the AMBER14SB/GAFF1.8 force field, we obtained an overall MUE of 1.17 kcal/mol and an overall RMSE of 1.50 kcal/mol for the 330 perturbations contained in this data set. They are comparable to the overall MUE of 0.9 kcal/mol and RMSE of 1.14 kcal/mol using their GPU free energy code (FEP+) and the OPLS2.1 force field combined with the REST2 enhanced sampling by Schrodinger, Inc. Notably, after we published our work, several other research groups reported their benchmarking results on the other free energy software using the same dataset.The third study of this thesis focuses on modeling the thermodynamics of transition metal (TM) ions binding to a protein. TM ions are very common in biology and are important in drug discovery as well, because many TM ions are in the active site of the protein where the inhibitors bind, for example, the histone deacetylase. While the structural details of TMs bound to metalloproteins are generally well understood via experimental and computational means; studies accurately describing the thermodynamics of TM ion binding are less common. Herein, we demonstrate that we can obtain accurate structural and absolute binding free energies of Co2+ and Ni2+ to the enzyme glyoxalase I (GlxI) using an optimized 12-6-4 (m12-6-4) potential. Optimizing the 12-6-4 potential to accurately model the interactions between the TMs and the binding site residues, as well as protonation state changes associated with TMs (un)binding, are found to be crucial. Given the success of this study, we are now in a position to explore more complicated processes associated with TM-based drug discovery.
Author: Kira A. Armacost
Publisher:
ISBN: 9780841298064
Category : Drug development
Languages : en
Pages :
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Book Description
"This book is about Free Energy Methods in Drug Discovery: Current State and Future Directions"--
Author: Roderick E Hubbard
Publisher: Royal Society of Chemistry
ISBN: 1847552544
Category : Medical
Languages : en
Pages : 279
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Book Description
Structure-based drug discovery is a collection of methods that exploits the ability to determine and analyse the three dimensional structure of biological molecules. These methods have been adopted and enhanced to improve the speed and quality of discovery of new drug candidates. After an introductory overview of the principles and application of structure-based methods in drug discovery, this book then describes the essential features of the various methods. Chapters on X-ray crystallography, NMR spectroscopy, and computational chemistry and molecular modelling describe how these particular techniques have been enhanced to support rational drug discovery, with discussions on developments such as high throughput structure determination, probing protein-ligand interactions by NMR spectroscopy, virtual screening and fragment-based drug discovery. The concluding chapters complement the overview of methods by presenting case histories to demonstrate the major impact that structure-based methods have had on discovering drug molecules. Written by international experts from industry and academia, this comprehensive introduction to the methods and practice of structure-based drug discovery not only illustrates leading-edge science but also provides the scientific background for the non-expert reader. The book provides a balanced appraisal of what structure-based methods can and cannot contribute to drug discovery. It will appeal to industrial and academic researchers in pharmaceutical sciences, medicinal chemistry and chemical biology, as well as providing an insight into the field for recent graduates in the biomolecular sciences.
Author: Javier Luque
Publisher: Royal Society of Chemistry
ISBN: 1849733538
Category : Medical
Languages : en
Pages : 443
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Book Description
This title covers a wide range of topics relevant to the development of drugs. It provides a comprehensive description of the major methodological strategies available for rational drug discovery.
Author: Vasanthanathan Poongavanam
Publisher: John Wiley & Sons
ISBN: 3527840737
Category : Science
Languages : en
Pages : 882
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Book Description
Computational Drug Discovery A comprehensive resource that explains a wide array of computational technologies and methods driving innovation in drug discovery Computational Drug Discovery: Methods and Applications (2 volume set) covers a wide range of cutting-edge computational technologies and computational chemistry methods that are transforming drug discovery. The book delves into recent advances, particularly focusing on artificial intelligence (AI) and its application for protein structure prediction, AI-enabled virtual screening, and generative modeling for compound design. Additionally, it covers key technological advancements in computing such as quantum and cloud computing that are driving innovations in drug discovery. Furthermore, dedicated chapters that addresses the recent trends in the field of computer aided drug design, including ultra-large-scale virtual screening for hit identification, computational strategies for designing new therapeutic modalities like PROTACs and covalent inhibitors that target residues beyond cysteine are also presented. To offer the most up-to-date information on computational methods utilized in computational drug discovery, it covers chapters highlighting the use of molecular dynamics and other related methods, application of QM and QM/MM methods in computational drug design, and techniques for navigating and visualizing the chemical space, as well as leveraging big data to drive drug discovery efforts. The book is thoughtfully organized into eight thematic sections, each focusing on a specific computational method or technology applied to drug discovery. Authored by renowned experts from academia, pharmaceutical industry, and major drug discovery software providers, it offers an overview of the latest advances in computational drug discovery. Key topics covered in the book include: Application of molecular dynamics simulations and related approaches in drug discovery The application of QM, hybrid approaches such as QM/MM, and fragment molecular orbital framework for understanding protein-ligand interactions Adoption of artificial intelligence in pre-clinical drug discovery, encompassing protein structure prediction, generative modeling for de novo design, and virtual screening. Techniques for navigating and visualizing the chemical space, along with harnessing big data to drive drug discovery efforts. Methods for performing ultra-large-scale virtual screening for hit identification. Computational strategies for designing new therapeutic models, including PROTACs and molecular glues. In silico ADMET approaches for predicting a variety of pharmacokinetic and physicochemical endpoints. The role of computing technologies like quantum computing and cloud computing in accelerating drug discovery This book will provide readers an overview of the latest advancements in computational drug discovery and serve as a valuable resource for professionals engaged in drug discovery.
Author: Kenneth M. Merz
Publisher: Cambridge University Press
ISBN: 0521887232
Category : Medical
Languages : en
Pages : 289
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Book Description
This book provides a complete snapshot of various experimental approaches to structure-based and ligand-based drug design and is illustrated with more than 200 images.
Author: Christoph Gorgulla
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
