Download or read book Structural and Functional Validation of S adenosylmethionine Decarboxylase as a Novel Drug Target in the Malaria Parasite Plasmodium Falciparum written by Dina Coertzen and published by . This book was released on 2014 with total page 236 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is considered the most prevailing human parasitic disease. Despite various chemotherapeutic interventions being available, the parasite responsible for the most lethal form of malaria, Plasmodium falciparum, is continuously developing resistance towards drugs targeted against it. This, therefore, necessitates the need for validation of new antimalarial development. Polyamine biosynthetic enzymes, particularly S-adenosylmethionine-L-decarboxylase (PfAdoMetDC), has been identified as a suitable drug target for protozoan parasitic diseases due to its essential role in cell proliferation. Furthermore, in Plasmodium polyamine biosynthesis, PfAdoMetDC is organised into a unique bifunctional complex with ornithine decarboxylase (PfAdoMetDC/ODC) covalently linked by a hinge region, distinguishing this enzyme as unique a drug target. However, inhibitors targeting this pathway have not been successful in clinical assessment, creating the need for further research in identifying novel inhibitors. This study focused on the structural and functional characterisation of protein-specific properties of the AdoMetDC domain in P. falciparum parasites, as well as identifying novel inhibitors targeting this enzyme as a potential antimalarial therapeutic intervention. In order to develop novel inhibitors specifically targeting PfAdoMetDC through a structure-based drug discovery approach, the three-dimensional structure is required. However, due to a lack of structural and functional characterisation, determination of the crystal structure has been challenging. Heterologous expression of monofunctional PfAdoMetDC was achieved from a wild-type construct of the PfAdoMetDC domain including the covalently linked hinge region. In chapter 2, deletion of a large non-homologous, low-complexity parasite-specific insert (A3) in monofunctional PfAdoMetDC resulted in an increased yield, purity and sample homogeneity, whilst maintaining protein functionality and structural integrity. However, truncation of the proposed non-essential hinge region resulted in low-level expression of insoluble protein aggregates and a complete loss of protein activity, indicating that the hinge region is essential for monofunctional PfAdoMetDC. However, in the absence of the three-dimensional PfAdoMetDC crystal structure, novel derivatives of a well-known AdoMetDC inhibitor, MDL73811, were tested for their activity against heterologous PfAdoMetDC, as well as their potency against P. falciparum parasites, in chapter 3. The compound Genz-644131 was identified as a lead inhibitor of PfAdoMetDC, however, the poor membrane permeability of the compound resulted in low in vitro activity. Drug permeability of Genz-644131 into P. falciparum infected erythrocytes and its potency was significantly improved by its encapsulation into a novel immunoliposome based drug delivery system. The results presented here provide essential information for development of a unique strategy in obtaining suffiecient levels of fully active recombinant PfAdoMetDC of sufficient purity for crystallisation studies and subsequent structure-based drug design efforts. The combination of Genz-644131 with the novel drug delivery system, which markedly improved its potency against PfAdoMetDC may proof to be a viable antimalarial chemotherapeutic strategy for future investigations.
Download or read book Modulation of Functional Properties of Bi functional S Adenosylmethionine Decarboxylase written by Suretha Roux and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is a global health threat that causes 300 500 million clinical cases annually, resulting in approximately 2 million deaths. Chemotherapy and prophylaxis are becoming less effective because of increasing drug resistance by the parasite. Resurgence of malaria calls for the development of mechanistically novel drugs. The bifunctional organization of the two rate-limiting enzymes, AdoMetDC and ODC, in the P. Falciparum polyamine pathway and the presence of six parasite-specific inserts, present potential target sites for novel Plasmodia-specific drugs. The inserts are species-specific, hydrophilic, low complexity segments and form non-globular domains. The inserts are involved in intra- and interdomain interactions, which are important for stability and activity of the bifunctional construct. This study investigated properties of the parasite-specific inserts, one being the mobility of the O1 insert and the other the secondary structures present in the parasitespecific inserts. It is postulated that the mobility of the O1 insert plays a role in either heterotetrameric complex formation of the bifunctional construct or that the O1 insert acts as a lid to the ODC active site, which is necessary for catalytic function. Successful mutagenesis of the O1 flanking Gly residues to Ala, rendered the O1 insert immobile. The probable immobility of the O1 insert had a detrimental effect on the activity of both the AdoMetDC and ODC domains of the bifunctional protein. Molecular dynamics studies showed that movement restriction of the insert caused a conformational change in the ODC monomers. The decrease of both domain activities upon movement restriction of the O1 insert suggests that the insert is involved in protein-protein interactions, which is communicated throughout the protein. In addition, the roles of selected, predicted secondary structures in the Hinge, O1 and O2 parasite-specific inserts were investigated.? -Helices were disrupted by the introduction of a Pro residue,? -plates were removed with deletion mutagenesis. The effects of the secondary structure alterations on protein activity were monitored in the bifunctional PfAdoMetDC/ODC protein. Both domain activities were affected by the disruptions, although the ODC domain was more sensitive to the small changes. The results obtained in this study showed that the secondary structures in the parasite-specific insert are important for activity of both the AdoMetDC and ODC domains of the bifunctional protein, possibly via interdomain protein-protein interactions. The delineation of essential intra- and interdomain protein-protein interactions presents possible interaction sites for disruptive molecules in the combat against malaria. Copyright.
Download or read book Delineation of Functional Roles of Parasite specific Inserts in the Malarial S adenosylmethionine Decarboxylase written by Marni Williams and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The polyamines putrescine, spermidine and spermine play essential roles in the proliferation and differentiation of most eukaryotic cells. Inhibition of the polyamine pathway is known to have antitumour and antiparasitic effects and? -difluoromethylornithine (DFMO), a polyamine biosynthesis inhibitor, is clinically used in the treatment of African sleeping sickness caused by Trypanosoma brucei gambiense. Ornithine decarboxylase (ODC) and Sadenosylmethionine decarboxylase (AdoMetDC) are the rate-limiting enzymes in polyamine metabolism. Usually, these enzymes are individually regulated, however, in the malaria parasite, Plasmodium falciparum, these enzymes are part of a unique bifunctional PfAdoMetDC/ODC protein. In addition, compared to homologous proteins, this malarial protein contains six unique parasite-specific inserted regions, which can be targeted with novel drugs. A modified restriction enzyme-mediated inverse PCR method was developed to delete the largest parasite-specific insert (411 bp) from the large PfAdoMetDC/ODC gene (4257 bp). The method was compared to existing deletion mutagenesis PCR protocols and was shown to be the most effective method (80% mutagenesis efficiency) as opposed to the 40% positively mutated clones obtained with the overlapping primer method in deleting a>100 bp region. The independent removal of all three the PfAdoMetDC domain parasite-specific inserts and subsequent activity analysis thereof showed that these inserts are essential for the catalytic activities of both the decarboxylase domains. Plasmodia conserved secondary structures within these inserts were identified and were also shown to be very important for domain activities, possibly through protein-protein interactions across and within the domains of the bifunctional complex for the efficient regulation of intracellular polyamine levels. The N-terminally located O1 insert in the PfODC domain is a highly conserved and structurally distinct insert, which is essential for both domain activities. Previous studies showed that the deletion of this insert prevents dimerisation of the PfODC monomers and as a result influences association of PfODC with the PfAdoMetDC domain to form the bifunctional 3̃30 kDa complex. In addition, immobilisation of the insert via the mutagenesis of flanking Gly residues and the disruption of a single conserved ; -helix within the insert severely affected both PfODC and PfAdoMetDC activities. It was thus hypothesised that the helix is involved in protein-protein interactions and the dimerisation of the PfODC domain. Size-exclusion chromatography of the monofunctional PfODC and bifunctional PfAdoMetDC/ODC proteins with disrupted helices resulted in the elution of only the monomeric (8̃5 kDa) and heterodimeric PfAdoMetDC/ODC (1̃60 kDa) proteins, respectively. The mono- and bifunctional wild type and immobile proteins eluted as both dimeric PfODC (1̃70 kDa) and heterotetrameric (3̃30 kDa) fractions as a result of intact protein-protein interactions. These results were subsequently exploited in the design and application of a parasite-specific, mechanistically novel, inhibitory peptide specific for this non-homologous insert in the bifunctional protein. A 1000x molar excess of a synthetic peptide, complementary to the ; -helix within the O1 insert but opposite in charge, resulted in a 4̃0% inhibition of the PfODC enzyme. This study thus provides a proof-of-principle for the use of an inhibitory peptide targeting a parasite-specific insert in the dimerisation interface of a uniquely bifunctional malarial protein.
Download or read book Structure based Drug Discovery Against a Novel Antimalarial Drug Target S adenosylmethionine Decarboxylase ornithine Decarboxylase written by Jonathan James Reynolds and published by . This book was released on 2012 with total page 208 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Biochemical and Structural Characterization of Novel Drug Targets Regulating Polyamine Biosynthesis in the Human Malaria Parasite Plasmodium Falciparum written by Marni Williams and published by . This book was released on 2011 with total page 368 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Modulation of Functional Properties of Bifunctional S adenosylmethionine Decarboxylase ornithine Decarboxylase of Plamodium Falciparum by Structural Motifs in Parasite specific Inserts written by Suretha Roux and published by . This book was released on 2006 with total page 178 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Automated Structural Annotation of the Malaria Proteome and Identification of Candidate Proteins for Modelling and Crystallization Studies written by Yolandi Joubert and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is the cause of over one million deaths per year, primarily in African children. The parasite responsible for the most virulent form of malaria, is Plasmodium falciparum. Protein structure plays a pivotal role in elucidating mechanisms of parasite functioning and resistance to anti-malarial drugs. Protein structure furthermore aids the determination of protein function, which can together with the structure be used to identify novel drug targets in the parasite. However, various structural features in P. falciparum proteins complicate the experimental determination of protein three dimensional structures. Furthermore, the presence of parasite-specific inserts results in reduced similarity of these proteins to orthologous proteins with experimentally determined structures. The lack of solved structures in the malaria parasite, together with limited similarities to proteins in the Protein Data Bank, necessitate genome-scale structural annotation of P. falciparum proteins. Additionally, the annotation of a range of structural features facilitates the identification of suitable targets for structural studies. An integrated structural annotation system was constructed and applied to all the predicted proteins in P. falciparum, Plasmodium vivax and Plasmodium yoelii. Similarity searches against the PDB, Pfam, Superfamily, PROSITE and PRINTS were included. In addition, the following predictions were made for the P. falciparum proteins: secondary structure, transmembrane helices, protein disorder, low complexity, coiled-coils and small molecule interactions. P. falciparum protein-protein interactions and proteins exported to the RBC were annotated from literature. Finally, a selection of proteins were threaded through a library of SCOP folds. All the results are stored in a relational PostgreSQL database and can be viewed through a web interface (http://deepthought.bi.up.ac.za:8080/Annotation). In order to select groups of proteins which fulfill certain criteria with regard to structural and functional features, a query tool was constructed. Using this tool, criteria regarding the presence or absence of all the predicted features can be specified. Analysis of the results obtained revealed that P. falciparum protein-interacting proteins contain a higher percentage of predicted disordered residues than non-interacting proteins. Proteins interacting with 10 or more proteins have a disordered content concentrated in the range of 60-100%, while the disorder distribution for proteins having only one interacting partner, was more evenly spread. Comparisons of structural and sequence features between the three species, revealed that P. falciparum proteins tend to be longer and vary more in length than the other two species. P. falciparum proteins also contained more predicted low complexity and disorder content than proteins from P. yoelii and P. vivax. P. falciparumprotein targets for experimental structure determination, comparative modeling and in silico docking studies were putatively identified based on structural features. For experimental structure determination, 178 targets were identi_ed. These targets contain limited contents of predicted transmembrane helix, disorder, coiled-coils, low complexity and signal peptide, as these features may complicate steps in the experimental structure determination procedure. In addition, the targets display low similarity to proteins in the PDB. Comparisons of the targets to proteins with crystal structures, revealed that the structures and predicted targets had similar sequence properties and predicted structural features. A group of 373 proteins which displayed high levels of similarity to proteins in the PDB, were identified as targets for comparitive modeling studies. Finally, 197 targets for in silico docking were identified based on predicted small molecule interactions and the availability of a 3D structure.
Download or read book Dissecting Mechanisms of Antimalarials Using CRISPR Cas9 Editing in Plasmodium Falciparum written by SooNee Tan and published by . This book was released on 2019 with total page 123 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria, caused by Plasmodium infections, continues to be a global disease of public health importance with 300 million annual cases and about 500,000 deaths. Continual emergence of resistance to commonly used antimalarials underscores the importance of finding new drug targets and new antimalarial drugs. Previously, the Rathod lab has established systematic approaches to study targets of antimalarials and resistance mechanisms with the use of in vitro selection methods and deep sequencing of selected mutants. There are some limitations with these approaches as deep sequencing data does not reveal the stepwise mechanism of mutagenesis and mutations observed from the sequencing result might not associate with the resistance phenotype. This thesis has multiple projects aimed to expand the molecular toolbox with genome manipulation using CRISPR/Cas9 technique. It will complement the current tools that we have in performing target identification/validation as well as understanding the mechanism of mutagenesis in malaria parasites. Ciprofloxacin is an antibacterial known to target bacterial DNA Gyrase. In some instances, ciprofloxacin has been used for malaria prophylaxis but little is known about the mode-of-action of ciprofloxacin in malaria parasites. In the first project, we aim to understand the essentiality of Plasmodium falciparum DNA gyrase A subunit (PfGyrA) and its relationship with ciprofloxacin. Based on bioinformatics analyses, PfGyr A and B subunits are known to contain apicoplast-targeting signals. To test the predicted localization of this enzyme in the apicoplast and the function of this enzyme at the subcellular level, a CRISPR/Cas9 gene-editing tool was used to disrupt PfGyrA. It is known that isopentenyl pyrophosphate (IPP) rescues malaria parasites from apicoplast-targeting inhibitors and indeed successful growth of Pf[delta]GyrA required chemical rescue with IPP. PfGyrA disruption was accompanied by loss of the plastid acyl-carrier protein (ACP) immunouorescnce and the plastid genome. Drug sensitivity assays revealed that a Pf[delta]GyrA clone, supplemented with IPP was less sensitive to antibacterial compounds (doxycycline and ciprofloxacin) but not the nuclear topoisomerase inhibitor (etoposide). In addition, at high concentrations, ciprofloxacin continued to inhibit IPP-rescued Pf[delta]GyrA suggesting that this drug has an additional target in P. falciparum. We concluded that PfGyrA is an apicoplast enzyme in malaria parasite and it is essential for blood-stage parasites. In the future, untangling the two possible inhibitory functions of ciprofloxacin in malaria parasites may reveal a new and important drug target. The second project aim involves target validation of a tetrahydroquinolone compound, BMS-388891. Previous publications from the lab showed that resistance to BMS-388891 arises from a single point mutation in either the protein farnesyl transferase (PFT) alpha or beta subunit. Although results indicated that a single point mutation on the PfPFT enzyme led to BMS-3888891 resistant parasites, whole genome sequencing on those mutants have yet to be done. To test that a single mutation is sufficient for parasite acquisition of resistance to BMS-388891, gene alteration with CRISPR/Cas9 tool was utilized to introduce a point mutation (Y837N, Y837S, or Y837C) on the PFT-[Beta]-subunit. The CRISPR-modified mutant parasites have shown an increase of 10-20 fold resistance to BMS-388891. This data is the first to formally demonstrate that a single point mutation on the Pfpft-[Beta]-subunit is sufficient for parasites to confer resistance to BMS-388891 compound. There are very few validated compound to target relationships and CRISPR/Cas9 technique will be a valuable tool in the malaria field. The third project aim involves the understanding of the mechanism of mutagenesis in malaria parasites. While it is known that amplification and point mutation are the possible outcomes of resistance selection, the order of the processes is less understood. Recent work by Guler et. al. points to a novel step-wise amplification mechanism in the malarial parasite response to DSM1 selection pressure. In these selected parasites, 25-30 kb regions surrounding the Pfdhodh locus were amplified. Taking advantage of the highly amplified Pfdhodh locus, we were able to introduce Pfpft-[alpha]-subunit into this region. This sets up future studies for us to dissect the step-wise resistance mechanism in malaria parasites. Overall, the utilization of CRISPR/Cas9 tool has allowed us to efficiently perform gene knockout, gene alteration and gene translocation. These applications not only enable us to prove for the first time the importance of the PfGyrA enzyme but also to directly confirm the causality of specific point mutations in BMS-388891 resistant parasites. The addition of CRISPR/Cas9 gene-editing to our systematic approach toolbox will ultimately aid in our understanding of how mutagenesis occurs in malaria parasites and allow us to expand our knowledge in the mode-of-action of different antimalarials in P. falciparum.
Download or read book Development of a Dynamic Receptor based Pharmacophore Model of Plasmodium Falciparum Spermidine Synthase for Selective Inhibitor Identification written by Pieter Buys Burger and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria affects the daily lives of more than 2 billion people worldwide and has been estimated to result in 300-500 million clinical cases annually leading to approximately 2 million deaths, mainly caused by the most virulent malaria species, Plasmodium falciparum. The lack of a vaccine and the rapid emergence and spread of drug resistant strains of P. falciparum, necessitate the development of new antimalarials and the identification and validation of new parasite-specific therapeutic targets. Numerous studies directed at interfering with the polyamine biosynthetic pathway in P. falciparum have shown its potential as a target for the development of a new class of antimalarials. The essential nature of P. falciparum spermidine synthase (PfSpdSyn), an enzyme in the polyamine pathway of the parasite warranted the further investigation to find novel lead compounds. The high cost and attrition rate of drug discovery has resulted in the implementation of smart drug discovery platforms in both academia and industry. The strategy implemented in this study involved the development of a dynamic receptor-based pharmacophore model (DPM) of PfSpdSyn complemented by a knowledge-based rational design strategy. The use of pharmacophore models to identify lead compounds has become increasingly popular over the last decade and has been shown to be a reliable method in the drug discovery process. The development of a DPM allows for the incorporation of protein exibility within the drug design process. This methodology results in a wealth of information of the chemical space of the active site and was incorporated in designing new inhibitors against PfSpdSyn using a knowledge-based rational design strategy. The active site of PfSpdSyn was subdivided into four binding regions (DPM1-DPM4) to allow for the identi cation of fragments binding within these speci c binding regions. DPMs representative of the chemical characteristics of each binding region were constructed and subsequently screened against the drug-like subset of the ZINC database. From the screens a total of nine compounds were selected for in vitro testing, complementing each other in exploring specific active site binding characteristics. From these compounds a new lead compound N-(3-aminopropyl)-cyclohexylamine (NAC: Ki 2.8 ; M) was identified for PfSpdSyn. NAC was specifically designed to bind in both the putrescine and decarboxylated adenosylmethionine cavities by chemically bridging the catalytic center and was confirmed by kinetic studies. NAC shows great potential for lead optimization to increase its binding affinity. This study then paves the way for lead optimization and possibly the development of a novel antimalarial. The development of a DPM for PfSpdSyn has seen the establishment of this methodology in the Bioinformatics and Computational Biology Unit, Department of Biochemistry at the University of Pretoria. It can be concluded that the development of a DPM complemented by a knowledge-based rational design strategy is an effective approach for the identification of novel lead compounds in the presence of a 3D target structure. This paves the way for more studies on both malaria and other drug targets using DPMs. Copyright.
Download or read book Encyclopedia of Malaria written by and published by Springer. This book was released on 2018-07-12 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Encyclopedia of Malaria represents a vast databank of information about the study of malaria. It provides an overview of the historical, rapid and significant developments that have occurred in malaria research, including the 2002 genome sequencing of Plasmodium falciparum and its mosquito vector, Anopheles gambiae. This work provides a concise source of up-to-date research findings in the form of definitions and essays and present comprehensive coverage of topics from history to findings to diagnosis and treatment, written by recognized malaria researchers with practical experience. It appeals to a diverse audience, including malaria researchers, teachers, investigators and public health professionals.
Download or read book Drug Resistance in Leishmania Parasites written by Alicia Ponte-Sucre and published by Springer Science & Business Media. This book was released on 2012-09-04 with total page 458 pages. Available in PDF, EPUB and Kindle. Book excerpt: One of the main problems concerning therapeutic tools for the treatment of parasitic diseases, including leishmaniasis, is that some field parasites are naturally resistant to the classical drugs; additionally, current therapies may select parasites prone to be resistant to the applied drugs. These features are (at least partially) responsible for the disappointing persistence of the disease and resultant deaths worldwide. This book provides a comprehensive view of the pathology of the disease itself, and of parasitic drug resistance, its molecular basis, consequences and possible treatments. Scientists both from academic fields and from the industry involved in biomedical research and drug design, will find in this book a valuable and fundamental guide that conveys the knowledge needed to understand and to improve the success in combating this disease worldwide.
Download or read book Handbook of Drug Nutrient Interactions written by Joseph I. Boullata and published by Springer Science & Business Media. This book was released on 2010-03-17 with total page 823 pages. Available in PDF, EPUB and Kindle. Book excerpt: Handbook of Drug-Nutrient Interactions, Second Edition is an essential new work that provides a scientific look behind many drug-nutrient interactions, examines their relevance, offers recommendations, and suggests research questions to be explored. In the five years since publication of the first edition of the Handbook of Drug-Nutrient Interactions new perspectives have emerged and new data have been generated on the subject matter. Providing both the scientific basis and clinical relevance with appropriate recommendations for many interactions, the topic of drug-nutrient interactions is significant for clinicians and researchers alike. For clinicians in particular, the book offers a guide for understanding, identifying or predicting, and ultimately preventing or managing drug-nutrient interactions to optimize patient care. Divided into six sections all chapters have been revised or are new to this edition. Chapters balance the most technical information with practical discussions and include outlines that reflect the content; discussion questions that can guide the reader to the critical areas covered in each chapter, complete definitions of terms with the abbreviation fully defined and consistent use of terms between chapters. The editors have performed an outstanding service to clinical pharmacology and pharmaco-nutrition by bringing together a multi-disciplinary group of authors. Handbook of Drug-Nutrient Interactions, Second Edition is a comprehensive up-to-date text for the total management of patients on drug and/or nutrition therapy but also an insight into the recent developments in drug-nutrition interactions which will act as a reliable reference for clinicians and students for many years to come.
Download or read book Drug Targets in Kinetoplastid Parasites written by Hemanta K. Majumder and published by Springer. This book was released on 2011-01-24 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The dreaded protozoal diseases caused by a number of Kinetoplastid parasites threaten mankind, as therapeutic tools for the treatment of most parasitic diseases are extremely limited. Development of commercially available vaccines is still far from reality, though research and trial programs continue. This book covers current research into drug therapeutics for the conditions caused by the parasites, which if viewed globally, pose an increasing threat to human health and welfare.
Download or read book Handbook of Sepsis written by W. Joost Wiersinga and published by Springer. This book was released on 2018-04-13 with total page 264 pages. Available in PDF, EPUB and Kindle. Book excerpt: This practically oriented book provides an up-to-date overview of all significant aspects of the pathogenesis of sepsis and its management, including within the intensive care unit. Readers will find information on the involvement of the coagulation and endocrine systems during sepsis and on the use of biomarkers to diagnose sepsis and allow early intervention. International clinical practice guidelines for the management of sepsis are presented, and individual chapters focus on aspects such as fluid resuscitation, vasopressor therapy, response to multiorgan failure, antimicrobial therapy, and adjunctive immunotherapy. The closing section looks forward to the coming decade, discussing novel trial designs, sepsis in low- and middle-income countries, and emerging management approaches. The book is internatio nal in scope, with contributions from leading experts worldwide. It will be of value to residents and professionals/practitioners in the fields of infectious diseases and internal medicine, as well as to GPs and medical students.
Download or read book Comprehensive Analysis of Parasite Biology written by Sylke Müller and published by John Wiley & Sons. This book was released on 2016-10-10 with total page 574 pages. Available in PDF, EPUB and Kindle. Book excerpt: Written and edited by experts in the field, this book brings together the current state of the art in phenotypic and rational, target-based approaches to drug discovery against pathogenic protozoa. The chapters focus particularly on virtual compounds and high throughput screening, natural products, computer-assisted drug design, structure-based drug design, mechanism of action identification, and pathway modelling. Furthermore, state-of the art "omics" technologies are described and currently studied enzymatic drug targets are discussed. Mathematical, systems biology-based approaches are introduced as new methodologies for dissecting complex aspects of pathogen survival mechanisms and for target identification. In addition, recently developed anti-parasitic agents targeting particular pathways, which serve as lead compounds for further drug development, are presented.
Download or read book Bacterial Resistance to Antibiotics written by Boyan B. Bonev and published by John Wiley & Sons. This book was released on 2019-06-10 with total page 288 pages. Available in PDF, EPUB and Kindle. Book excerpt: AN AUTHORITATIVE SURVEY OF CURRENT RESEARCH INTO CLINICALLY USEFUL CONVENTIONAL AND NONCONVENTIONAL ANTIBIOTIC THERAPEUTICS Pharmaceutically-active antibiotics revolutionized the treatment of infectious diseases, leading to decreased mortality and increased life expectancy. However, recent years have seen an alarming rise in the number and frequency of antibiotic-resistant "Superbugs." The Centers for Disease Control and Prevention (CDC) estimates that over two million antibiotic-resistant infections occur in the United States annually, resulting in approximately 23,000 deaths. Despite the danger to public health, a minimal number of new antibiotic drugs are currently in development or in clinical trials by major pharmaceutical companies. To prevent reverting back to the pre-antibiotic era—when diseases caused by parasites or infections were virtually untreatable and frequently resulted in death—new and innovative approaches are needed to combat the increasing resistance of pathogenic bacteria to antibiotics. Bacterial Resistance to Antibiotics – From Molecules to Man examines the current state and future direction of research into developing clinically-useful next-generation novel antibiotics. An internationally-recognized team of experts cover topics including glycopeptide antibiotic resistance, anti-tuberculosis agents, anti-virulence therapies, tetracyclines, the molecular and structural determinants of resistance, and more. Presents a multidisciplinary approach for the optimization of novel antibiotics for maximum potency, minimal toxicity, and appropriated degradability Highlights critical aspects that may relieve the problematic medical situation of antibiotic resistance Includes an overview of the genetic and molecular mechanisms of antibiotic resistance Addresses contemporary issues of global public health and longevity Includes full references, author remarks, and color illustrations, graphs, and charts Bacterial Resistance to Antibiotics – From Molecules to Man is a valuable source of up-to-date information for medical practitioners, researchers, academics, and professionals in public health, pharmaceuticals, microbiology, and related fields.
Download or read book Medicinal Chemistry of Anticancer Drugs written by Carmen Avendaño and published by Elsevier. This book was released on 2015-06-11 with total page 767 pages. Available in PDF, EPUB and Kindle. Book excerpt: Medicinal Chemistry of Anticancer Drugs, Second Edition, provides an updated treatment from the point of view of medicinal chemistry and drug design, focusing on the mechanism of action of antitumor drugs from the molecular level, and on the relationship between chemical structure and chemical and biochemical reactivity of antitumor agents. Antitumor chemotherapy is a very active field of research, and a huge amount of information on the topic is generated every year. Cytotoxic chemotherapy is gradually being supplemented by a new generation of drugs that recognize specific targets on the surface or inside cancer cells, and resistance to antitumor drugs continues to be investigated. While these therapies are in their infancy, they hold promise of more effective therapies with fewer side effects. Although many books are available that deal with clinical aspects of cancer chemotherapy, this book provides a sorely needed update from the point of view of medicinal chemistry and drug design. Presents information in a clear and concise way using a large number of figures Historical background provides insights on how the process of drug discovery in the anticancer field has evolved Extensive references to primary literature
