Bacterial Enzymes As Targets For Drug Discovery
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Bacterial Enzymes As Targets For Drug Discovery
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Author : Punit Kaur
language : en
Publisher: Academic Press
Release Date : 2024-11-01
Bacterial Enzymes As Targets For Drug Discovery written by Punit Kaur and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2024-11-01 with Medical categories.
Bacterial Enzymes as Targets for Drug Discovery: Meeting the Challenges of Antibiotic Resistance addresses the gap between medical microbiology, structural biology, and genomic science in the development of new antibacterial drug development. This book consolidates detailed profiling of bacterial target enzyme families for the drug discovery process and methodologies for use and validation of the potential drug targets. The content covers the foundations of antibiotic drug discovery process and focuses on bacterial enzymes as drug targets, building a bridge between microbiology, structural biology, and genomic science. This is the ideal reference for antibiotic drug discovery researchers in the pharma industry and academia. Biochemists, microbiologists, and medicinal chemists will also benefit from this books’ content.
Drug Design Of Zinc Enzyme Inhibitors
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Author : Claudiu T. Supuran
language : en
Publisher: John Wiley & Sons
Release Date : 2009-10-22
Drug Design Of Zinc Enzyme Inhibitors written by Claudiu T. Supuran and has been published by John Wiley & Sons this book supported file pdf, txt, epub, kindle and other format this book has been release on 2009-10-22 with Medical categories.
Brings together functional and structural informationrelevant to the design of drugs targeting zinc enzymes The second most abundant transition element in living organisms, zinc spans all areas of metabolism, with zinc-containing proteins offering both established and potential drug targets. Drug Design of Zinc-Enzyme Inhibitors brings together functional and structural information relevant to these zinc-containing targets. With up-to-date overviews of the latest developments field, this unique and comprehensive text enables readers to understand zinc enzymes and evaluate them in a drug design context. With contributions from the leaders of today's research, Drug Design of Zinc-Enzyme Inhibitors covers such key topics as: Major drug targets like carbonic anhydrases, matrix metalloproteinases, bacterial proteases, angiotensin-converting enzyme, histone deacetylase, and APOBEC3G Roles of recently discovered zinc-containing isozymes in cancer, obesity, epilepsy, pain management, malaria, and other conditions Cross reactivity of zinc-enzyme inhibitors and activators The extensive use of X-ray crystallography and QSAR studies for understanding zinc-containing proteins Clinical applications An essential resource for the discovery and development of new drug molecules, Drug Design of Zinc-Enzyme Inhibitors gives researchers, professionals, students, and academics the foundation to understand and work with zinc enzyme inhibitors and activators.
Drug Discovery Targeting Drug Resistant Bacteria
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Author : Prashant Kesharwani
language : en
Publisher: Academic Press
Release Date : 2020-05-29
Drug Discovery Targeting Drug Resistant Bacteria written by Prashant Kesharwani and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2020-05-29 with Business & Economics categories.
Drug Discovery Targeting Drug-Resistant Bacteria explores the status and possible future of developments in fighting drug-resistant bacteria. The book covers the majority of microbial diseases and the drugs targeting them. In addition, it discusses the potential targeting strategies and innovative approaches to address drug resistance. It brings together academic and industrial experts working on discovering and developing drugs targeting drug-resistant (DR) bacterial pathogens. New drugs active against drug-resistant pathogens are discussed, along with new strategies being used to discover molecules acting via new modes of action. In addition, alternative therapies such as peptides and phages are included. Pharmaceutical scientists, microbiologists, medical professionals, pathologists, researchers in the field of drug discovery, infectious diseases and microbial drug discovery both in academia and in industrial settings will find this book helpful. Written by scientists with extensive industrial experience in drug discovery Provides a balanced view of the field, including its challenges and future directions Includes a special chapter on the identification and development of drugs against pathogens which exhibit the potential to be used as weapons of war
Investigation Of Narrow Spectrum Targets In Antibacterial Drug Discovery
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Author : Jesse Jones
language : en
Publisher:
Release Date : 2019
Investigation Of Narrow Spectrum Targets In Antibacterial Drug Discovery written by Jesse Jones and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2019 with categories.
Background: Significant concerns are associated with the use of broad-spectrum antibacterial agents, including collateral eradication of beneficial bacteria from the human microbiome, the onset of antibacterial-associated infections, and continued emergence of antibacterial drug resistance. As such, a critical need for novel and selective antibacterial targets exists. The investigation of two such targets, each pertaining to the highly concerning infections caused by streptococcal species and Clostridioides difficile, are presented herein. Bacterial topoisomerase I represents a potentially promising narrow-spectrum target as studies have arisen demonstrating its essentiality in bacterial species lacking the only other type IA topoisomerase (topoisomerase III). Additionally, recent studies demonstrating the essentiality of the fabK gene expressing enoyl-ACP reductase II (FabK) in C. difficile indicate its significant potential as a narrow-spectrum target. Presented here are data characterizing and validating both the TopoI and FabK enzymes as novel antibacterial targets via the implementation of an array of drug discovery techniques, including structural studies, biochemical assay development and application, and inhibitor screening and testing. Methods: An assortment of drug discovery techniques were employed for the targeting of SmTopoI and CdFabK, including different protein expression and purification techniques; X-ray crystallography; various biophysical and biochemical techniques for target characterization, validation, and drug screening; and different lead development and optimization studies. Results: The respective genes for SmTopoI and CdFabK have been cloned, and the expression and purification of various constructs of each target have been carried out and optimized for further analysis. The crystal structure of SmTopoI_N65 has been determined to 2.06 Å and diffracting CdFabK crystals (3.5 Å) have been attained. A high-throughput plate-based biochemical fluorescence kinetic assay has been optimized for screening against the CdFabK enzyme. Furthermore, activity and modality of inhibition assessment of small-molecule inhibitors of the CdFabK enzyme have been conducted, including phenylimidazole and benzothiazole compounds. Phenylimidazole analogues have been found to display micromolar inhibitory activity against CdFabK, and a benzothiazole analogue has been found to display nanomolar inhibitory activity against the target. Conclusions: The SmTopoI and CdFabK enzymes present potentially novel, narrow- spectrum antibacterial drug targets, and substantial progress has been made toward the rational targeting of these two enzymes. Of particular note, the first structure of a Topo I fragment from a gram-positive organism, S. mutans, has been determined. Enzymology and inhibitor studies have been conducted supporting the druggability of CdFabK and indicating the potential for selective inhibition of CdFabK.
Enzybiotics
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Author : Tomas G. Villa
language : en
Publisher: John Wiley & Sons
Release Date : 2010-01-05
Enzybiotics written by Tomas G. Villa and has been published by John Wiley & Sons this book supported file pdf, txt, epub, kindle and other format this book has been release on 2010-01-05 with Science categories.
Presents the latest research and applications for a new, promising approach to fighting infectious diseases Enzybiotics is a promising way of fighting bacterial or fungal infectious diseases by using viruses or viral-derived lysins. Drawing from the fields of medicinal chemistry, microbiology, genetics, and biochemistry, this book presents the state of the science in enzybiotics research, fully exploring its emerging therapeutic applications. The book begins with four chapters that review the potential applications, possible advantages, and phylogeny of enzybiotics. Next, the book explores: A new approach to controlling infections using Gram-negative bacteria Bacteriophage holins and their membrane-disrupting activity Anti-staphylococcal lytic enzymes Membrane-targeted enzybiotics Design of phage cocktails for therapy from a host-range point of view Novel methods to identify new enzybiotics Genetically modified phages that deliver suicidal genes to target bacteria The authors, all active enzybiotics researchers, offer a variety of perspectives, the benefit of their own hands-on investigations, as well as a thorough review and analysis of the current literature. As more and more bacteria become resistant to antibiotics, the development of new disease-fighting agents has become essential. This book demonstrates the full potential of the emerging field of enzybiotics to control infectious diseases. Moreover, it will serve as a springboard for new research and the development of new therapeutics.
Current Developments In The Detection And Control Of Multi Drug Resistance
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Author : Sanket Kaushik
language : en
Publisher: Bentham Science Publishers
Release Date : 2022-07-26
Current Developments In The Detection And Control Of Multi Drug Resistance written by Sanket Kaushik and has been published by Bentham Science Publishers this book supported file pdf, txt, epub, kindle and other format this book has been release on 2022-07-26 with Medical categories.
The rise in the incidence of infections is caused by multi drugresistant (MDR) bacteria, it is essential to elucidate the basic mechanism ofantibiotic resistance to discover effective methods for diagnosis and treatmentof infections. The use of pathogen-specific probes offers a faster alternative forpathogen detection and could improve the diagnosis of infection. High resolutionmelting analysis techniques are useful for the detection of multi drugresistant pathogens. Rational Structural Based Drug Design is a common methodto identify a lead compound and take it forward for further developments.This book provides information about recent strategies involved in thediagnosis and treatment of infections caused by MDR bacteria. The volume coversthe use of molecular probes for the quantification of pathogenic bacteria, alongwith other techniques mentioned above. Chapters also cover the use of identificationof novel drug targets from the Lipid A biosynthesis and also from quorum sensingmediated biofilm formation in MDR bacteria. Chapters also cover herbal alternatives for the treatment of MDRbacteria like the use of Cassiaaungustifolia in treatment of various diseases. The reference is suitablefor biomedical students, cellular and molecular biologists.
Pharmaceuticals From Microbes
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Author : Divya Arora
language : en
Publisher: Springer
Release Date : 2019-02-12
Pharmaceuticals From Microbes written by Divya Arora and has been published by Springer this book supported file pdf, txt, epub, kindle and other format this book has been release on 2019-02-12 with Science categories.
This book deals with the noteworthy advancement in the production of bioactive metabolites from microbes and their pharmacological significance. It highlights the pharmacological potential of marine microbes and endophytic fungi and their bioactive secondary metabolites. Emphasis is also given on the significance of probiotics and their specialized molecules in human health and disease as well as their role in dietary intervention for reducing the risk of non-alcoholic fatty liver disease. This work also serves as excellent reference material for researchers, students and academicians in the field of natural product chemistry, pharmacology and applied microbiology.
Development Of Selective Inhibitors Against Metabolic Enzymes Involved In Aspartate Pathway For Antibiotic Development
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Author : Bharani Thangavelu
language : en
Publisher:
Release Date : 2016
Development Of Selective Inhibitors Against Metabolic Enzymes Involved In Aspartate Pathway For Antibiotic Development written by Bharani Thangavelu and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2016 with Amino acids categories.
Aspartate-ß-semialdehyde dehydrogenase (ASADH) is located at the first branch point in the aspartate metabolic pathway, which leads to the biosynthesis of several essential amino acids and important metabolites. This pathway is present only in plants and microbes but absent in mammals. The Aspartate pathway is crucial for bacteria for various metabolic processes and the microbial enzymes involved in this pathway are attractive targets for new antibiotic and antifungal compounds. The structures of ASADHs have been determined from Gram-positive bacteria, Gram-negative bacteria and fungal species. These enzymes share the same substrate binding and active site catalytic groups; however they show different inhibition patterns when screened against low molecular weight fragment libraries. Methionine is a sulfur-containing amino acid that is synthesized via a branch point in the aspartate metabolic pathway. S-adenosyl methionine (AdoMet) is subsequently synthesized from methionine, and plays a critical role in the transfer of methyl groups to various biomolecules, including DNA, proteins and small-molecule secondary metabolites. The branch point that leads to the synthesis of methionine and S-adenosyl methionine starts with the activation of the hydroxyl group of homoserine. The mode of activation of homoserine differs from plants to microorganisms, as well as within different microbial systems. At this point, depending on the species, at least three different activation routes have been identified. In addition, the route of sulfur assimilation in these systems can also vary from species to species. Homoserine acyl transferases catalyze the primary routes to homoserine activation in microbes, and these enzymes are members of the a/ß hydrolase superfamily. While the two different families of homoserine acyl transferases use the same kinetic and chemical mechanisms to catalyze this related reaction, they do so by using significantly different overall structures, as well as subtle differences in their closely related active site structures. In all fungi, and in many Gram-positive bacterial species such as Bacillus, Brevibacterium and Corynebacterium, an acetyl group is transferred to homoserine from acetyl-CoA to form O-acetyl homoserine (OAH) catalyzed by homoserine transacetylase (HTA) and coded by the met2 gene. In most enteric bacteria, including E. coli and other Gram-negative facultative and anaerobic bacteria, a succinyl group is transferred to homoserine from succinyl-CoA to form O-succinylhomoserine (OSH) catalyzed by homoserine transsuccinylase (HTS). The catalytic activity of both HTS and HTA has been shown to be regulated by coordinated feedback inhibition by both L-methionine and AdoMet. No organism has been identified to date that contains the genes for both acyltransferases. In addition to their variant in species distribution, these two enzymes display virtually no primary sequence similarity and also show significant structural differences. Since this pathway produces metabolites that play a number of critical biochemical roles in microorganisms, and because of the complete absence of related enzymes in mammals, the enzymes in this pathway represent novel targets for future antibiotic drug development. As a second project within this dissertation, development of enzyme inhibitors for the treatment of a rare neurological disorder is studied. Aspartate N-acetyl transferase (ANAT), an enzyme which catalyzes the N-acetyl aspartate (NAA). NAA is a major source of acetyl groups for lipid synthesis during brain development. Canavan disease (CD) is a rare, but fatal autosomal-recessive neurodegenerative disease caused by mutations in the acy2 gene that leads to the deficiency in the encoded aspartoacylase (ASPA), the enzyme responsible for the deacetylation of NAA in the brain. Recent work has shown that a knockout of the Nat8l gene that codes for ANAT leads to a reversal of the CNS demyelination in an animal model of CD. An approach in which selective ANAT inhibitors are used to adjust brain NAA levels back into the physiological range has the potential to treat the symptoms of CD without introducing increased risks. In the present study we describe the crystal structure of Staphylococcus aureus HTA and several approaches, including fragment based drug discovery, docking studies, kinetic and crystal structure studies which were combined to identify and characterize selective inhibitors of ASADH. The initial phthalate based inhibitors were modified by employing coupling reactions around the secondary amine, and systematically produced a series of inhibitors against our target enzyme. Structure-guided development of these lead compounds has now produced potent inhibitors of our target enzyme, with superior selectivity observed between the Gram-negative and Gram-positive orthologs of ASADH. This combined approach of inhibitor design, along with kinetic and structural characterization, illustrates the potential for potent drug development against these essential enzymes.
The Development And Application Of A Fluorescence Based Activity Assay For Bacterial N5 Cair Mutase
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Author : Marcella F. Sharma
language : en
Publisher:
Release Date : 2020
The Development And Application Of A Fluorescence Based Activity Assay For Bacterial N5 Cair Mutase written by Marcella F. Sharma and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2020 with Pharmacology categories.
ABSTRACT THE DEVELOPMENT AND APPLICATION OF A FLUORESCENCE BASED ASSAY FOR BACTERIAL N5-CAIR MUTASE by MARCELLA F. SHARMA May 2020 Advisor: Dr. Steven M. Firestine Major: Pharmaceutical Sciences Degree: Master of Science The lack of development in the antimicrobial drug pipeline has led us to focus on novel drug targets. The bacterial enzymes of the de novo purine biosynthesis pathway serve as a novel target for antimicrobial drug discovery. Within this pathway, there is a divergence between humans and bacteria in the step that converts 5-aminoimidazole ribonucleotide (AIR) to carboxy-5-aminoimidazole ribonucleotide (CAIR). Humans require only one enzyme, AIR carboxylase to accomplish this conversion while bacteria utilize two distinctive enzymes, N5-CAIR synthetase and N5-CAIR mutase. Unfortunately, a robust activity-based assay does not exist for N5-CAIR mutase. To address this problem, a novel, fluorescence based activity screen was developed in the Firestine lab that is based on the reaction of enzymatically produced AIR with fluorescein-labeled isatin (I-FITC). Reaction of AIR with I-FITC results in a large increase in the fluorescence signal. The assay is robust (Z0́9 0.79) and we have used it to conduct a small screen of 80 fragments. No reproducible hits were identified. A high-throughput screen was conducted on N5-CAIR mutase using the 2,400 compound Microsource Spectrum library. Again, no verified hits were identified. Future studies will explore larger, focused fragment library to identify inhibitors of N5-CAIR mutase.
Burger S Medicinal Chemistry Drug Discovery And Development
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Author : Donald J. Abraham
language : en
Publisher:
Release Date : 2021
Burger S Medicinal Chemistry Drug Discovery And Development written by Donald J. Abraham and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2021 with Drug development categories.
"Burger's is a flagship reference source for medicinal chemists and pharmaceutical professionals. This updated and expanded 8th edition has been thoroughly revised and improved to incorporate the concepts of drug hunting along with its existing coverage of the entire process of drug discovery and development. Bringing in a new and expert editorial board, this new edition updates existing chapters and adds 35 new ones, with topics including: opioid addiction treatments, antibody and gene therapy for cancer, blood-brain barrier, HIV treatments, and industrial-academic collaboration structures"--