Combining Computational Chemistry, Synthesis and Enzymology for the Design of Covalent Inhibitors Applied to Prolyl Oligopeptidase Inhibition PDF Download
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Author: Stephane De Cesco
Publisher:
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Languages : en
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"Medicinal chemistry and structure-based drug design are largely focused on non-covalent interactions. Shape complementarity and optimization of hydrogen-bonds and hydrophobic interactions have been the gold standard of most drug design and development projects. In the recent years, light has been shed on the prevalence of covalent linkage between natural or synthetic ligands and their associated biological targets. Indeed, with the advance of analytical techniques, it has been found that widely used drugs such as aspirin act by covalently modifying their targets. Despite this established past and present prevalence, there is still reluctance to incorporate covalent inhibitors in drug discovery programs. In this thesis, we started by looking at what it would take to successfully incorporate covalent interactions into the design of potential drugs. Specific considerations have been reviewed at different stages of a classical drug discovery project, from target selection to lead optimization. From this perspective, we applied this knowledge to the discovery and development of prolyl oligopeptidase (POP) covalent inhibitors. POP is a post-proline cleaving serine protease involved in various conditions such as neurodegenerative disorders (e.g. Alzheimer's disease) and cancer. Different strategies were employed, going from virtual screening to computer-aided rational design to guide the discovery of covalent POP inhibitors. The syntheses of those designed inhibitors were conceived with effectiveness and diversity in mind. In order to fully understand the reaction pathway a mechanistic study on the acylation/intramolecular Diels-Alder step was carried out. This led to the discovery of diverse POP inhibitors in the low nanomolar affinity range (Ki = 1-50 nM). We have also looked at the effect of different reactive functional groups and fluorine atoms activating these groups on the inhibition of POP. In order to gain further information on covalent inhibition, we decided to investigate the binding kinetics of our inhibitors. Methods have been developed to provide experimental measurement of binding kinetics and a preliminary structure kinetics relationship has been established. Lastly, we turned our efforts towards exploration of dual inhibition of POP and fibroblast activation protein-[alpha] (FAP) which is a proline peptidase involved in the development of various cancers. A chiral scaffold has been designed and synthesized in order to probe the geometrical requirement associated to the inhibition of those two enzymes. This work led to the discovery of potent POP inhibitors (Ki = 15-20 nM) and provided additional insights in the requirements for FAP inhibition." --
Author: Stephane De Cesco
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
"Medicinal chemistry and structure-based drug design are largely focused on non-covalent interactions. Shape complementarity and optimization of hydrogen-bonds and hydrophobic interactions have been the gold standard of most drug design and development projects. In the recent years, light has been shed on the prevalence of covalent linkage between natural or synthetic ligands and their associated biological targets. Indeed, with the advance of analytical techniques, it has been found that widely used drugs such as aspirin act by covalently modifying their targets. Despite this established past and present prevalence, there is still reluctance to incorporate covalent inhibitors in drug discovery programs. In this thesis, we started by looking at what it would take to successfully incorporate covalent interactions into the design of potential drugs. Specific considerations have been reviewed at different stages of a classical drug discovery project, from target selection to lead optimization. From this perspective, we applied this knowledge to the discovery and development of prolyl oligopeptidase (POP) covalent inhibitors. POP is a post-proline cleaving serine protease involved in various conditions such as neurodegenerative disorders (e.g. Alzheimer's disease) and cancer. Different strategies were employed, going from virtual screening to computer-aided rational design to guide the discovery of covalent POP inhibitors. The syntheses of those designed inhibitors were conceived with effectiveness and diversity in mind. In order to fully understand the reaction pathway a mechanistic study on the acylation/intramolecular Diels-Alder step was carried out. This led to the discovery of diverse POP inhibitors in the low nanomolar affinity range (Ki = 1-50 nM). We have also looked at the effect of different reactive functional groups and fluorine atoms activating these groups on the inhibition of POP. In order to gain further information on covalent inhibition, we decided to investigate the binding kinetics of our inhibitors. Methods have been developed to provide experimental measurement of binding kinetics and a preliminary structure kinetics relationship has been established. Lastly, we turned our efforts towards exploration of dual inhibition of POP and fibroblast activation protein-[alpha] (FAP) which is a proline peptidase involved in the development of various cancers. A chiral scaffold has been designed and synthesized in order to probe the geometrical requirement associated to the inhibition of those two enzymes. This work led to the discovery of potent POP inhibitors (Ki = 15-20 nM) and provided additional insights in the requirements for FAP inhibition." --
Author: Janice Lawandi
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Publisher: Academic Press
ISBN: 0128232463
Category : Science
Languages : en
Pages : 300
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Book Description
Annual Report on Medicinal Chemistry series, highlights new advances in the field with this new volume presenting interesting chapters. Each chapter is written by an international board of authors. Provides the authority and expertise of leading contributors from an international board of authors Presents the latest release in the Annual Report on Medicinal Chemistry series Updated release includes the latest information on The Design of Covalent-Based Inhibitors
Author: Weiping Zheng
Publisher: Royal Society of Chemistry
ISBN: 1839161973
Category : Science
Languages : en
Pages : 211
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Author: Jerry Kurian
Publisher:
ISBN:
Category :
Languages : en
Pages :
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"Over the past decade, an increasing interest for covalent inhibition - modulating enzyme activity through covalently binding to it - as a drug design strategy has been observed. To aid in the development of covalent inhibitors, techniques which allow for prediction and characterization of activity must be made available. Knowledge about covalent inhibitor strength, activation energies, residence times and mechanisms must be obtained to allow for successful covalent drug development methodologies. In this thesis, we assessed whether two serine proteases, prolyl oligopeptidase (POP) and fibroblast activation protein (FAP), react similarly with respect to kinetics and thermodynamics in relation to the electrophile on the covalent ligand. To streamline such investigations, we exploited computational techniques as a method for prediction of covalent druggability - the ability of an enzyme to be inhibited through covalent means. We investigated the influence of different electrophilic groups (aldehyde, boronic acid and nitrile) on potency and binding kinetics with a series of truncated analogous inhibitors of POP, using quantum mechanical (QM) methods, such as the quantum chemical cluster approach (QCCA). The direct correlation between inhibitor reactivity and residence time was demonstrated through the QCCA and was further supported by experimental studies in the Moitessier group. The validated computational method was then applied to FAP, which has previously been thought to be less reactive than POP. Computations in this work predicted that the truncated ligands binding to POP result in a larger energy lowering compared to FAP. Similar computational techniques were used to evaluate the atomic basis for this difference in reactivity through a detailed analysis of hydrogen bond lengths and angles in the active site of POP. This analysis was supplemented with calculations on the difference in basicity of the catalytic histidine in POP and FAP, responsible for removing the proton off the catalytic serine. The stronger the base, the easier the catalytic serine residue can be deprotonated and hence more reactive and available for nucleophilic attack. The data suggests that the histidine in POP may be more basic than in FAP, supporting the claim that the serine in POP may be more reactive than in FAP." --
Author: Jessica Plescia
Publisher:
ISBN:
Category :
Languages : en
Pages :
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"Cancer will affect 50% of Canadians in their lifetimes. Although many biological targets have been linked to cancer, the focus of this dissertation is on two homologous serine proteases implicated in epithelial cancers: prolyl oligopeptidase (POP) and fibroblast activation protein alpha (FAP), associated with angiogenesis and tumour growth and expansion, respectively. The research outlined in this thesis consists of utilizing the computational platform FORECASTER, developed by the Moitessier research group, to conduct virtual screenings and docking-guided drug design of dual POP-FAP reversible covalent inhibitors. In the past, our group focused on inhibitors of POP for its implication in neurodegenerative conditions, including Parkinson's and Alzheimer's diseases. Because of its more recent link to epithelial cancers, which make up approximately 90% of adult cancers, along with FAP, our group has shifted our focus to dual inhibition. Targeting both enzymes simultaneously has shown to hinder tumour growth and expansion and has even been suggested to have a synergistic effect in vivo.In this dissertation, we explore several methodologies to obtain potent inhibitors. We begin with an integrative study among medicinal chemists, biophysicists, and computational chemists, in which we aim to determine the best electrophilic warhead for targeting POP and FAP. Our collaborative study led us to discover that boronic acids and esters are the optimal group in terms of reactivity and residence time. We further explore boronic acid drugs in this dissertation's introduction. Next, docking-guided virtual optimization of a known potent POP inhibitor, followed by a structure-activity relationship study, led to discovery of single-digit nanomolar potent POP inhibitors compounds with two-step syntheses. Further docking-guided peptidomimetics studies and synthetic development have led our group to our first bicyclic inhibitor that exhibits nanomolar POP-FAP potency and improves upon a drug that failed in Phase III trials. We are further developing this hit and hope to progress to pre-clinical studies. This study in particular led to the exploration of a complex mechanism required for its synthesis. Finally, a comprehensive virtual screening led to the discovery of a bicyclic borinic ester scaffold that yields very promising molecular docking predictions. We are currently in the late stages of the synthesis of this potential dual inhibitor"--
Author: S. Balamurugan
Publisher: John Wiley & Sons
ISBN: 1119654718
Category : Computers
Languages : en
Pages : 354
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Book Description
COMPUTATION IN BIOINFORMATICS Bioinformatics is a platform between the biology and information technology and this book provides readers with an understanding of the use of bioinformatics tools in new drug design. The discovery of new solutions to pandemics is facilitated through the use of promising bioinformatics techniques and integrated approaches. This book covers a broad spectrum of the bioinformatics field, starting with the basic principles, concepts, and application areas. Also covered is the role of bioinformatics in drug design and discovery, including aspects of molecular modeling. Some of the chapters provide detailed information on bioinformatics related topics, such as silicon design, protein modeling, DNA microarray analysis, DNA-RNA barcoding, and gene sequencing, all of which are currently needed in the industry. Also included are specialized topics, such as bioinformatics in cancer detection, genomics, and proteomics. Moreover, a few chapters explain highly advanced topics, like machine learning and covalent approaches to drug design and discovery, all of which are significant in pharma and biotech research and development. Audience Researchers and engineers in computation biology, information technology, bioinformatics, drug design, biotechnology, pharmaceutical sciences.
Author: Steven Howard
Publisher: Royal Society of Chemistry
ISBN: 1782625658
Category : Medical
Languages : en
Pages : 314
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Book Description
Fragment-based drug discovery is a rapidly evolving area of research, which has recently seen new applications in areas such as epigenetics, GPCRs and the identification of novel allosteric binding pockets. The first fragment-derived drug was recently approved for the treatment of melanoma. It is hoped that this approval is just the beginning of the many drugs yet to be discovered using this fascinating technique. This book is written from a Chemist's perspective and comprehensively assesses the impact of fragment-based drug discovery on a wide variety of areas of medicinal chemistry. It will prove to be an invaluable resource for medicinal chemists working in academia and industry, as well as anyone interested in novel drug discovery techniques.
Author: Yanyan Li
Publisher: Springer
ISBN: 1493910108
Category : Medical
Languages : en
Pages : 113
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Book Description
Lasso peptides form a growing family of fascinating ribosomally-synthesized and post-translationally modified peptides produced by bacteria. They contain 15 to 24 residues and share a unique interlocked topology that involves an N-terminal 7 to 9-residue macrolactam ring where the C-terminal tail is threaded and irreversibly trapped. The ring results from the condensation of the N-terminal amino group with a side-chain carboxylate of a glutamate at position 8 or 9, or an aspartate at position 7, 8 or 9. The trapping of the tail involves bulky amino acids located in the tail below and above the ring and/or disulfide bridges connecting the ring and the tail. Lasso peptides are subdivided into three subtypes depending on the absence (class II) or presence of one (class III) or two (class I) disulfide bridges. The lasso topology results in highly compact structures that give to lasso peptides an extraordinary stability towards both protease degradation and denaturing conditions. Lasso peptides are generally receptor antagonists, enzyme inhibitors and/or antibacterial or antiviral (anti-HIV) agents. The lasso scaffold and the associated biological activities shown by lasso peptides on different key targets make them promising molecules with high therapeutic potential. Their application in drug design has been exemplified by the development of an integrin antagonist based on a lasso peptide scaffold. The biosynthesis machinery of lasso peptides is therefore of high biotechnological interest, especially since such highly compact and stable structures have to date revealed inaccessible by peptide synthesis. Lasso peptides are produced from a linear precursor LasA, which undergoes a maturation process involving several steps, in particular cleavage of the leader peptide and cyclization. The post-translational modifications are ensured by a dedicated enzymatic machinery, which is composed of an ATP-dependent cysteine protease (LasB) and a lactam synthetase (LasC) that form an enzymatic complex called lasso synthetase. Microcin J25, produced by Escherichia coli AY25, is the archetype of lasso peptides and the most extensively studied. To date only around forty lasso peptides have been isolated, but genome mining approaches have revealed that they are widely distributed among Proteobacteria and Actinobacteria, particularly in Streptomyces, making available a rich resource of novel lasso peptides and enzyme machineries towards lasso topologies.
Author: Laszlo Polgar
Publisher: CRC Press
ISBN: 9780849369018
Category : Medical
Languages : en
Pages : 236
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Book Description
A uniform treatment of the four protease groups and a discussion of the differences and similarities in their action is presented in this important new publication. Serine, cysteine, aspartate, and zinc proteases are systematically discussed by nomenclature, evolution, specificity and their regulatory role. The chemistry of the peptide bond, including the catalysis of ester and peptide hydrolyses, is explained. For each protease group the emphasis is placed on the structure and function. Kinetics, enzyme modifications, isotope effects, subzero temperature investigations, nuclear magnetic resonance measurements, X-ray diffraction data, binding of transition-state analogs, zymogen activation, and site-specific mutagenesis are combined to rationalize the action of proteases. Both natural and synthetic inhibitors are considered because of their importance in mechanistic studies and drug design.
