DOCSLIB.ORG

By Abraham Heifets a Thesis Submitted in Conformity with the Requirements

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
By Abraham Heifets a Thesis Submitted in Conformity with the Requirements AUTOMATED SYNTHETIC FEASIBILITY ASSESSMENT:ADATA-DRIVEN DERIVATION OF COMPUTATIONAL TOOLS FOR MEDICINAL CHEMISTRY by Abraham Heifets A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Computer Science University of Toronto c Copyright 2014 by Abraham Heifets Abstract Automated Synthetic Feasibility Assessment: A Data-driven Derivation of Computational Tools for Medicinal Chemistry Abraham Heifets Doctor of Philosophy Graduate Department of Computer Science University of Toronto 2014 The planning of organic syntheses, a critical problem in chemistry, can be directly modeled as resource- constrained branching plans in a discrete, fully-observable state space. Despite this clear relationship, the full artillery of artificial intelligence has not been brought to bear on this problem due to its inherent complexity and multidisciplinary challenges. In this thesis, I describe a mapping between organic synthesis and heuristic search and build a planner that can solve such problems automatically at the undergraduate level. Along the way, I show the need for powerful heuristic search algorithms and build large databases of synthetic information, which I use to derive a qualitatively new kind of heuristic guidance. ii Contents Relation to published work xi 1 Introduction 1 2 Prolegomena to any future automated synthesis planning 6 2.1 Search . .6 2.2 AND/OR graph search algorithms . .9 2.2.1 AO* . 10 2.2.2 Learning in Depth-First Search (LDFS) . 12 2.2.3 The question of cycle semantics . 13 2.2.4 Proof Number Search (PNS) . 15 2.2.5 PN* . 19 2.2.6 Proof Disproof Search (PDS) . 21 2.2.7 Depth-First Proof Number and variants (DFPN, DFPN+, DFPN(r), DFPN-TCA, and DFPN-SNDA) . 21 2.3 The shapes of chemistry . 25 2.4 Challenges of organic synthesis . 27 2.5 Automated organic synthesis planners . 29 2.5.1 LHASA and its variants (interactive synthesis planners) . 29 2.5.2 Noninteractive synthesis planners . 31 2.6 Heuristics . 33 2.6.1 Complexity-based . 36 2.6.2 Fragment-based . 38 2.6.3 Machine learning and retrosynthetic analysis . 40 2.7 Reaction libraries . 41 iii 2.8 The critical need for search guidance . 47 3 A declarative description of chemistry 49 3.1 Definitions . 49 4 Retrosynthetic search algorithms 55 4.1 Introduction . 55 4.2 A Proof Number Search-based Solver . 57 4.3 Constructing a Public Chemistry Benchmark . 62 4.4 Results and Discussion . 63 4.5 Chapter Conclusion and Future Work . 65 5 Compilation of synthesis and chemical data 66 5.1 SCRIPDB . 66 5.2 Discussion . 71 5.2.1 Patents as a source of chemical images . 71 5.2.2 Patents as biomedical literature . 72 5.2.3 Patents as a reaction database . 72 5.2.4 Patents as a bioisostere catalog . 73 5.3 Chapter Conclusion and Future Work . 73 6 Domain-specific heuristics for synthetic feasibility 75 6.1 Introduction . 75 6.1.1 Humans, eh? . 77 6.1.2 Objective measures of synthetic feasibility . 80 6.2 Materials and Methods . 81 6.2.1 Data collection . 81 6.2.2 Data cleaning . 87 6.2.3 Data labeling . 88 6.2.4 Data modeling . 90 6.3 Results . 92 6.4 Discussion . 95 6.5 Chapter Conclusion and Future Work . 98 7 Summary & Conclusion 100 iv Appendices 103 A Glossary 104 B Which molecules should be built? 107 B.1 Introduction . 107 B.2 System and methods . 111 B.2.1 Correspondence of bound ligands . 111 B.2.2 Ligand alignment . 113 B.2.3 Residue cluster extraction via clique detection . 115 B.3 Results and discussion . 116 B.3.1 Heme . 117 B.3.2 Nicotinamide adenine dinucleotide . 120 B.4 Chapter Conclusion and Future Work . 126 Bibliography 127 v List of Figures 2.1 Cyclical AND/OR graphs. Semicircles connect paths in a single hyperedge. Double circles in- dicate goal states. The examples are deliberately simple; equivalent yet more-realistic examples may be generated by replacing simple arcs with larger subgraphs. 14 2.2 If a descendant node can be reached via multiple paths, then Equations 2.1 and 2.2 are no longer correct. An example schematic when a node has repeated precursors showing the (dis)proof counts will be incorrect. In this case, there are only 3 leaf nodes but the root reports a count of4................................................... 18 2.3 Graph history interaction problem from Kishimoto and Muller¨ (2004). Assume node D is a loss for the player at the root. Node B is an AND node, marked by an semicircle connecting its out arcs. Nodes C, G, and H are AND nodes as well but are not marked because they have a single outgoing arc. 24 2.4 Aspirin. Vertices labeled C, H, or O denote carbon, hydrogen, and oxygen atoms, respectively. Edges drawn with single lines denote single bonds and double lines represent double bonds. Typ- ically, bonds to hydrogen are not drawn. 26 2.5 Esterification reaction of an alcohol active site with an anhydride active site to produce an ester. Atoms in the molecular fragments are numbered to help the reader track bond changes. When atomic labels are omitted, the vertex is presumed to be a carbon atom with sufficient hydrogens to total 4 bonds. Reaction conditions have been omitted for simplicity. 26 2.6 Synthesis of aspirin (right column) from carbon dioxide, sodium hydroxide, phenol, acetic acid and ketene starting materials (left column) via the precursor molecules, salicylic acid (top mid) and acetic anhydride (bottom mid). The final aspirin-forming step is an application of the esteri- fication reaction depicted in Fig 2.5. 26 2.7 Palytoxin, a 409-atom molecule synthesized in 1994 (Suh and Kishi, 1994). Bonds depicted as wedges indicate the bond is angled out of the plane of the paper toward the reader. Bonds depicted as dashes indicate the bond is angled away from the reader. 28 vi 2.8 Example from Todd (2005). Structure (40) depicts the quinone Diels-Alder reaction, while (41)- (43) show natural products that had been synthesized using the quinone Diels-Alder. LHASA does not apply the quinone DA to these cases. 30 2.9 8 step synthesis from Takahashi et al. (1990). Molecular complexity proceeds nonmonotonically. 32 2.10 Figure 19 from Boda et al. (2007) depicting minimum, maximum, and average synthetic acces- sibility scores by five medicinal chemists. Structures are sorted by average score. Molecules of particularly wide score disagreement are labeled. Most molecules have scores of 4 ± 1 and many have ranges which overlap. 35 2.11 Figure 7 from Huang et al. (2011) depicting minimum, maximum, and average synthetic accessi- bility scores by five medicinal chemists. Structures are sorted by average score. Most molecules have scores of 4 ± 1 and many have ranges which overlap. 35 2.12 Example comparison of synthetic complexity measures, taken from Barone and Chanon (2001). Synthetic progress is nonmonotonic. 37 2.13 Reaction example from Pirok et al. (2006) depicting a Friedel-Crafts Acylation reaction. Ad- ditional properties specify the charge necessary at the active site for the reaction to complete. Problematic compounds are excluded with additional patterns. 42 2.14 Diels-Alder example from Wilcox and Levinson (1986). Lines 1 and 4 show two reactions. Lines 2 and 3 are the MXC and CXC, respectively, for the first reaction. Line 5 shows the maximum common substructure from the two reactions (note the activating electron-withdrawing oxygen on the dieneophile). 44 2.15 Example from Law et al. (2009). Figure (a) depicts a sample reaction, while (b) and (c) show an extracted core and extended core, respectively. Compare to the MXC and CXC from Figure 2.14. Law et al. note that the non-chemically-essential atom 2 is correctly not included in the extended core; in contrast, a bond radius approach such as (Satoh and Funatsu, 1999) would have included it. 46 4.1 The benchmark target molecules. Images generated directly from the problem definition using OpenBabel O’Boyle et al. (2011a). 58 4.2 Computer-generated Atorvastatin synthesis matching the synthesis reported in Brower et al. (1992) and Roth (2002). ..
Load more

Recommended publications
  • Philosophy of Science and Philosophy of Chemistry
    Philosophy of Science and Philosophy of Chemistry Jaap van Brakel Abstract: In this paper I assess the relation between philosophy of chemistry and (general) philosophy of science, focusing on those themes in the philoso- phy of chemistry that may bring about major revisions or extensions of cur- rent philosophy of science. Three themes can claim to make a unique contri- bution to philosophy of science: first, the variety of materials in the (natural and artificial) world; second, extending the world by making new stuff; and, third, specific features of the relations between chemistry and physics. Keywords : philosophy of science, philosophy of chemistry, interdiscourse relations, making stuff, variety of substances . 1. Introduction Chemistry is unique and distinguishes itself from all other sciences, with respect to three broad issues: • A (variety of) stuff perspective, requiring conceptual analysis of the notion of stuff or material (Sections 4 and 5). • A making stuff perspective: the transformation of stuff by chemical reaction or phase transition (Section 6). • The pivotal role of the relations between chemistry and physics in connection with the question how everything fits together (Section 7). All themes in the philosophy of chemistry can be classified in one of these three clusters or make contributions to general philosophy of science that, as yet , are not particularly different from similar contributions from other sci- ences (Section 3). I do not exclude the possibility of there being more than three clusters of philosophical issues unique to philosophy of chemistry, but I am not aware of any as yet. Moreover, highlighting the issues discussed in Sections 5-7 does not mean that issues reviewed in Section 3 are less im- portant in revising the philosophy of science.
    [Show full text]
  • Open Data, Open Source, and Open Standards in Chemistry: the Blue Obelisk Five Years On" Journal of Cheminformatics Vol
    Oral Roberts University Digital Showcase College of Science and Engineering Faculty College of Science and Engineering Research and Scholarship 10-14-2011 Open Data, Open Source, and Open Standards in Chemistry: The lueB Obelisk five years on Andrew Lang Noel M. O'Boyle Rajarshi Guha National Institutes of Health Egon Willighagen Maastricht University Samuel Adams See next page for additional authors Follow this and additional works at: http://digitalshowcase.oru.edu/cose_pub Part of the Chemistry Commons Recommended Citation Andrew Lang, Noel M O'Boyle, Rajarshi Guha, Egon Willighagen, et al.. "Open Data, Open Source, and Open Standards in Chemistry: The Blue Obelisk five years on" Journal of Cheminformatics Vol. 3 Iss. 37 (2011) Available at: http://works.bepress.com/andrew-sid-lang/ 19/ This Article is brought to you for free and open access by the College of Science and Engineering at Digital Showcase. It has been accepted for inclusion in College of Science and Engineering Faculty Research and Scholarship by an authorized administrator of Digital Showcase. For more information, please contact [email protected]. Authors Andrew Lang, Noel M. O'Boyle, Rajarshi Guha, Egon Willighagen, Samuel Adams, Jonathan Alvarsson, Jean- Claude Bradley, Igor Filippov, Robert M. Hanson, Marcus D. Hanwell, Geoffrey R. Hutchison, Craig A. James, Nina Jeliazkova, Karol M. Langner, David C. Lonie, Daniel M. Lowe, Jerome Pansanel, Dmitry Pavlov, Ola Spjuth, Christoph Steinbeck, Adam L. Tenderholt, Kevin J. Theisen, and Peter Murray-Rust This article is available at Digital Showcase: http://digitalshowcase.oru.edu/cose_pub/34 Oral Roberts University From the SelectedWorks of Andrew Lang October 14, 2011 Open Data, Open Source, and Open Standards in Chemistry: The Blue Obelisk five years on Andrew Lang Noel M O'Boyle Rajarshi Guha, National Institutes of Health Egon Willighagen, Maastricht University Samuel Adams, et al.
    [Show full text]
  • EXPLORING NEW ASYMMETRIC REACTIONS CATALYSED by DICATIONIC Pd(II) COMPLEXES
    EXPLORING NEW ASYMMETRIC REACTIONS CATALYSED BY DICATIONIC Pd(II) COMPLEXES A DISSERTATION FOR THE DEGREE OF DOCTOR OF PHILOSOPHY FROM IMPERIAL COLLEGE LONDON BY ALEXANDER SMITH MAY 2010 DEPARTMENT OF CHEMISTRY IMPERIAL COLLEGE LONDON DECLARATION I confirm that this report is my own work and where reference is made to other research this is referenced in text. ……………………………………………………………………… Copyright Notice Imperial College of Science, Technology and Medicine Department Of Chemistry Exploring new asymmetric reactions catalysed by dicationic Pd(II) complexes © 2010 Alexander Smith [email protected] This publication may be distributed freely in its entirety and in its original form without the consent of the copyright owner. Use of this material in any other published works must be appropriately referenced, and, if necessary, permission sought from the copyright owner. Published by: Alexander Smith Department of Chemistry Imperial College London South Kensington campus, London, SW7 2AZ UK www.imperial.ac.uk ACKNOWLEDGEMENTS I wish to thank my supervisor, Dr Mimi Hii, for her support throughout my PhD, without which this project could not have existed. Mimi’s passion for research and boundless optimism have been crucial, turning failures into learning curves, and ultimately leading this project to success. She has always been able to spare the time to advise me and provide fresh ideas, and I am grateful for this patience, generosity and support. In addition, Mimi’s open-minded and multi-disciplinary approach to chemistry has allowed the project to develop in new and unexpected directions, and has fundamentally changed my attitude to chemistry. I would like to express my gratitude to Dr Denis Billen from Pfizer, who also provided a much needed dose of optimism and enthusiasm in the early stages of the project, and managed to arrange my three month placement at Pfizer despite moving to the US as the department closed.
    [Show full text]
  • Open Data, Open Source and Open Standards in Chemistry: the Blue Obelisk five Years On
    Open Data, Open Source and Open Standards in chemistry: The Blue Obelisk ¯ve years on Noel M O'Boyle¤1 , Rajarshi Guha2 , Egon L Willighagen3 , Samuel E Adams4 , Jonathan Alvarsson5 , Richard L Apodaca6 , Jean-Claude Bradley7 , Igor V Filippov8 , Robert M Hanson9 , Marcus D Hanwell10 , Geo®rey R Hutchison11 , Craig A James12 , Nina Jeliazkova13 , Andrew SID Lang14 , Karol M Langner15 , David C Lonie16 , Daniel M Lowe4 , J¶er^omePansanel17 , Dmitry Pavlov18 , Ola Spjuth5 , Christoph Steinbeck19 , Adam L Tenderholt20 , Kevin J Theisen21 , Peter Murray-Rust4 1Analytical and Biological Chemistry Research Facility, Cavanagh Pharmacy Building, University College Cork, College Road, Cork, Co. Cork, Ireland 2NIH Center for Translational Therapeutics, 9800 Medical Center Drive, Rockville, MD 20878, USA 3Division of Molecular Toxicology, Institute of Environmental Medicine, Nobels vaeg 13, Karolinska Institutet, 171 77 Stockholm, Sweden 4Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of Cambridge, Lens¯eld Road, CB2 1EW, UK 5Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24 Uppsala, Sweden 6Metamolecular, LLC, 8070 La Jolla Shores Drive #464, La Jolla, CA 92037, USA 7Department of Chemistry, Drexel University, 32nd and Chestnut streets, Philadelphia, PA 19104, USA 8Chemical Biology Laboratory, Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702, USA 9St. Olaf College, 1520 St. Olaf Ave., North¯eld, MN 55057, USA 10Kitware, Inc., 28 Corporate Drive, Clifton Park, NY 12065, USA 11Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA 12eMolecules Inc., 380 Stevens Ave., Solana Beach, California 92075, USA 13Ideaconsult Ltd., 4.A.Kanchev str., So¯a 1000, Bulgaria 14Department of Engineering, Computer Science, Physics, and Mathematics, Oral Roberts University, 7777 S.
    [Show full text]
  • Peptide Chemistry up to Its Present State
    Appendix In this Appendix biographical sketches are compiled of many scientists who have made notable contributions to the development of peptide chemistry up to its present state. We have tried to consider names mainly connected with important events during the earlier periods of peptide history, but could not include all authors mentioned in the text of this book. This is particularly true for the more recent decades when the number of peptide chemists and biologists increased to such an extent that their enumeration would have gone beyond the scope of this Appendix. 250 Appendix Plate 8. Emil Abderhalden (1877-1950), Photo Plate 9. S. Akabori Leopoldina, Halle J Plate 10. Ernst Bayer Plate 11. Karel Blaha (1926-1988) Appendix 251 Plate 12. Max Brenner Plate 13. Hans Brockmann (1903-1988) Plate 14. Victor Bruckner (1900- 1980) Plate 15. Pehr V. Edman (1916- 1977) 252 Appendix Plate 16. Lyman C. Craig (1906-1974) Plate 17. Vittorio Erspamer Plate 18. Joseph S. Fruton, Biochemist and Historian Appendix 253 Plate 19. Rolf Geiger (1923-1988) Plate 20. Wolfgang Konig Plate 21. Dorothy Hodgkins Plate. 22. Franz Hofmeister (1850-1922), (Fischer, biograph. Lexikon) 254 Appendix Plate 23. The picture shows the late Professor 1.E. Jorpes (r.j and Professor V. Mutt during their favorite pastime in the archipelago on the Baltic near Stockholm Plate 24. Ephraim Katchalski (Katzir) Plate 25. Abraham Patchornik Appendix 255 Plate 26. P.G. Katsoyannis Plate 27. George W. Kenner (1922-1978) Plate 28. Edger Lederer (1908- 1988) Plate 29. Hennann Leuchs (1879-1945) 256 Appendix Plate 30. Choh Hao Li (1913-1987) Plate 31.
    [Show full text]
  • Synthesis and Applications of Derivatives of 1,7-Diazaspiro[5.5
    Synthesis and Applications of Derivatives of 1,7-Diazaspiro[5.5]undecane. A Thesis Submitted by Joshua J. P. Almond-Thynne In partial fulfilment of the requirements for the degree of Doctor of Philosophy Department of Chemistry Imperial College London South Kensington London, SW7 2AZ October 2017 1 Declaration of Originality I, Joshua Almond-Thynne, certify that the research described in this manuscript was carried out under the supervision of Professor Anthony G. M. Barrett, Imperial College London and Doctor Anastasios Polyzos, CSIRO, Australia. Except where specific reference is made to the contrary, it is original work produced by the author and neither the whole nor any part had been submitted before for a degree in any other institution Joshua Almond-Thynne October 2017 Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. 2 Abstract Spiroaminals are an understudied class of heterocycle. Recently, the Barrett group reported a relatively mild approach to the most simple form of spiroaminal; 1,7-diazaspiro[5.5]undecane (I).i This thesis consists of the development of novel synthetic methodologies towards the spiroaminal moiety. The first part of this thesis focuses on the synthesis of aliphatic derivatives of I through a variety of methods from the classic Barrett approach which utilises lactam II, through to de novo bidirectional approaches which utilise diphosphate V and a key Horner-Wadsworth- Emmons reaction with aldehyde VI.
    [Show full text]
  • Lecture 1: Strategies and Tactics in Organic Synthesis
    Massachusetts Institute of Technology Organic Chemistry 5.511 October 3, 2007 Prof. Rick L. Danheiser Lecture 1: Strategies and Tactics in Organic Synthesis Retrosynthetic Analysis The key to the design of efficient syntheses ". the grand thing is to be able to reason backwards. That is a very useful accomplishment, and a very easy "The end is where we start from...." one, but people do not practice it much." T. S. Eliot, in "The Four Quartets" Sherlock Holmes, in "A Study in Scarlet" Strategy Tactics overall plan to achieve the means by which plan ultimate synthetic target is implemented intellectual experimental retrosynthetic planning synthetic execution TRANSFORMS REACTIONS Target Precursor Precursor Target Definitions Retron Structural unit that signals the application of a particular strategy algorithm during retrosynthetic analysis. Transform Imaginary retrosynthetic operation transforming a target molecule into a precursor molecule in a manner such that bond(s) can be reformed (or cleaved) by known or reasonable synthetic reactions. Strategy Algorithm Step-by-step instructions for performing a retrosynthetic operation. "...even in the earliest stages of the process of simplification of a synthetic problem, the chemist must make use of a particular form of analysis which depends on the interplay between structural features that exist in the target molecule and the types of reactions or synthetic operations available from organic chemistry for the modification or assemblage of structural units. The synthetic chemist has learned by experience to recognize within a target molecule certain units which can be synthesized, modified, or joined by known or conceivable synthetic operations...it is convenient to have a term for such units; the term "synthon" is suggested.
    [Show full text]
  • On the Redundancy of Natural Products Public Databases and Where to Find Data in 2020 - a Review on Natural Products Databases
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 25 December 2019 doi:10.20944/preprints201912.0332.v1 On the redundancy of natural products public databases and where to find data in 2020 - a review on natural products databases Dr. Maria Sorokina (ORCID 0000-0001-9359-7149) ​ ​ Prof. Dr. Christoph Steinbeck (ORCID 0000-0001-6966-0814) ​ ​ Institute for Inorganic and Analytical Chemistry Friedrich-Schiller-University Lessingstr. 8 07743 Jena Abstract Natural products (NPs) have been the centre of attention of the scientific community in the last decencies and the interest around them continues to grow incessantly. As a consequence, in the last 20 years, there was a rapid multiplication of various databases and collections as generalistic or thematic resources for NP information. In this review, we establish a complete overview of these resources, and the numbers are overwhelming: over 120 different NP databases and collections were published and re-used since 2000. 98 of them are still somehow accessible and only 50 are open access. The latter include not only databases but also big collections of NPs published as supplementary material in scientific publications and collections that were backed up in the ZINC database for commercially-available compounds. Some databases, even published relatively recently are already not accessible anymore, which leads to a dramatic loss of data on NPs. The data sources are presented in this manuscript, together with the comparison of the content of open ones. With this review, we also compiled the open-access natural compounds in one single dataset a COlleCtion of Open NatUral producTs (COCONUT), which is available on Zenodo and contains structures and sparse annotations for over 400000 non-redundant NPs, which makes it the biggest open collection of NPs available to this date.
    [Show full text]
  • The Role of Conformational Dynamics in Isocyanide Hydratase Catalysis
    University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Theses and Dissertations in Biochemistry Biochemistry, Department of Spring 4-15-2020 THE ROLE OF CONFORMATIONAL DYNAMICS IN ISOCYANIDE HYDRATASE CATALYSIS Medhanjali Dasgupta University of Nebraska - Lincoln, [email protected] Follow this and additional works at: https://digitalcommons.unl.edu/biochemdiss Part of the Biochemistry Commons, Biophysics Commons, Microbiology Commons, and the Structural Biology Commons Dasgupta, Medhanjali, "THE ROLE OF CONFORMATIONAL DYNAMICS IN ISOCYANIDE HYDRATASE CATALYSIS" (2020). Theses and Dissertations in Biochemistry. 29. https://digitalcommons.unl.edu/biochemdiss/29 This Article is brought to you for free and open access by the Biochemistry, Department of at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Theses and Dissertations in Biochemistry by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. THE ROLE OF CONFORMATIONAL DYNAMICS IN ISOCYANIDE HYDRATASE CATALYSIS by Medhanjali Dasgupta A DISSERTATION Presented to the Faculty of The Graduate College at the University of Nebraska In partial Fulfillment of Requirements For the Degree of Doctor of Philosophy Major: Biochemistry Under the Supervision of Professor Mark A. Wilson Lincoln, Nebraska May 2020 THE ROLE OF CONFORMATIONAL DYNAMICS IN ISOCYANIDE HYDRATASE CATALYSIS Medhanjali Dasgupta, Ph.D. University of Nebraska, 2020 Advisor: Dr. Mark. A. Wilson Post-translational modification of cysteine residues can regulate protein function and is essential for catalysis by cysteine-dependent enzymes. Covalent modifications neutralize charge on the reactive cysteine thiolate anion and thus alter the active site electrostatic environment. Although a vast number of enzymes rely on cysteine modification for function, precisely how altered structural and electrostatic states of cysteine affect protein dynamics, which in turn, affects catalysis, remains poorly understood.
    [Show full text]
  • [2.2]Paracyclophanes- Structure and Reactivity Studies Von Der
    Syntheses of Functionalised [2.2]Paracyclophanes- Structure and Reactivity Studies Von der Gemeinsamen Naturwissenschaftlichen Fakultät der Technischen Universität Carolo Wilhelmina zu Braunschweig zur Erlangung des Grades eines Doktors der Naturwissenschaften (Dr.rer.nat.) genehmigte D i s s e r t a t i o n von Swaminathan Vijay Narayanan aus Chennai (Madras) / India 1. Referent: Prof. Dr. Dr. h. c. Henning Hopf 2. Referentin: Prof. Dr. Monika Mazik eingereicht am: 20. Jan 2005 mündliche Prüfung (Disputation) am: 29. März 2005 Druckjahr 2005 Vorveröffentlichungen der Dissertation Teilergebnisse aus dieser Arbeit wurden mit Genehmigung der Gemeinsamen Naturwissenschaft-lichen Fakultät, vertreten durch die Mentorin oder den Mentor/die Betreuerin oder den Betreuer der Arbeit, in folgenden Beiträgen vorab veröffentlicht: Publikationen K. El Shaieb, V. Narayanan, H. Hopf, I. Dix, A. Fischer, P. G. Jones, L. Ernst & K. Ibrom.: 4,15-Diamino[2.2]paracyclophane as a starting material for pseudo-geminally substituted [2.2]paracyclophanes. Eur. J. Org. Chem.: 567-577 (2003). Die vorliegende Arbeit wurde in der Zeit von Oktober 2001 bis Januar 2004 am Institut für Organische Chemie der Technischen Universität Braunschweig unter der Leitung von Prof. Dr. Dr. h.c. Henning Hopf angefertigt. It is my great pleasure to express my sincere gratitude to Prof. Dr. Henning Hopf for his support, encouragement and guidance throughout this research work. I thank him a lot for his invaluable ideas and remarks which made this study very interesting. I admire deep from my heart his energetic way of working and his brilliant ideas which made possible this research work to cover a vast area.
    [Show full text]
  • Cheminformatics for Genome-Scale Metabolic Reconstructions
    CHEMINFORMATICS FOR GENOME-SCALE METABOLIC RECONSTRUCTIONS John W. May European Molecular Biology Laboratory European Bioinformatics Institute University of Cambridge Homerton College A thesis submitted for the degree of Doctor of Philosophy June 2014 Declaration This thesis is the result of my own work and includes nothing which is the outcome of work done in collaboration except where specifically indicated in the text. This dissertation is not substantially the same as any I have submitted for a degree, diploma or other qualification at any other university, and no part has already been, or is currently being submitted for any degree, diploma or other qualification. This dissertation does not exceed the specified length limit of 60,000 words as defined by the Biology Degree Committee. This dissertation has been typeset using LATEX in 11 pt Palatino, one and half spaced, according to the specifications defined by the Board of Graduate Studies and the Biology Degree Committee. June 2014 John W. May to Róisín Acknowledgements This work was carried out in the Cheminformatics and Metabolism Group at the European Bioinformatics Institute (EMBL-EBI). The project was fund- ed by Unilever, the Biotechnology and Biological Sciences Research Coun- cil [BB/I532153/1], and the European Molecular Biology Laboratory. I would like to thank my supervisor, Christoph Steinbeck for his guidance and providing intellectual freedom. I am also thankful to each member of my thesis advisory committee: Gordon James, Julio Saez-Rodriguez, Kiran Patil, and Gos Micklem who gave their time, advice, and guidance. I am thankful to all members of the Cheminformatics and Metabolism Group.
    [Show full text]
  • Retrosynthetic Analysis and Synthetic Planning
    Retrosynthetic Analysis and Synthetic Planning Vancomycin is an antibiotic used against bacteria that cause 2:24 PM food poisoning. 1 Life’s Perspectives Planning a Journey to the Unknown 2:24 PM 2 Retrosynthetic Analysis Definition Retrosynthetic analysis (retrosynthesis) is a technique for planning a synthesis, especially of complex organic molecules, whereby the complex target molecule (TM) is reduced into a sequence of progressively simpler structures along a pathway which ultimately leads to the identification of a simple or commercially available starting material (SM) from which a chemical synthesis can then be developed. Retrosynthetic analysis is based on known reactions (e.g the Wittig reaction, oxidation, reduction etc). The synthetic plan generated from the retrosynthetic analysis will be the roadmap to guide the synthesis of the target molecule. 2:24 PM 3 Synthetic Planning Definition Synthesis is a construction process that involves converting simple or commercially available molecules into complex molecules using specific reagents associated with known reactions in the retrosynthetic scheme. Syntheses can be grouped into two broad categories: (i) Linear syntheses 2:24 PM (ii)Convergent syntheses 4 Linear Synthesis Definition In linear synthesis, the target molecule is synthesized through a series of linear transformations. Since the overall yield of the synthesis is based on the single longest route to the target molecule, by being long, a linear synthesis suffers a lower overall yield. The linear synthesis is fraught with failure for its lack of flexibility leading to potential large losses in the material already invested in the synthesis at the time of failure. 2:24 PM 5 Convergent Synthesis Definition In convergent synthesis, key fragments of the target molecule are synthesized separately or independently and then brought together at a later stage in the synthesis to make the target molecule.
    [Show full text]