Bioorganic and Medicinal Chemistry

CHEM30432 Bioorganic and Medicinal Chemistry 10 Semester 2 Undergraduate Level 6 John Gardiner Unit coordinator Department of Chemistry 1 FHEQ level (Framework for Higher Education Qualifications) ' Last part of a Bachelors ' European Credit Transfer & Accumulation System Rating : 5.0 <div>This unit covers three areas:  (i) Aspects of nucleic acid structure, biological function / uses and chemical synthesis; (ii) The use of computational chemistry in rational drug design; and (iii) Enzyme structure and behaviour, with introduction to enzyme mechanism examples, and important secondary metabolite biosynthesis chemistry (terpenes, steroids and alkaloids).  </div>  This unit covers three areas:  (i) Aspects of nucleic acid structure, biological function / uses and chemical synthesis; (ii) The use of computational chemistry in rational drug design; and(iii) Enzyme structure and behaviour, with introduction to enzyme mechanism examples, and important secondary metabolite biosynthesis chemistry (terpenes, steroids and alkaloids).   The unit aims to:<ul><li>Provide an understanding of nuclei acid structure and the chemistry involved in the biosynthesis, reactivity and chemical synthesis and applications of nuclei acids.</li><li>Discuss the use of computational chemistry in rational drug design.</li><li>Provide an understanding of the organic chemistry that underlies biochemical processes, including enzyme catalysis and molecular recognition, an introduction to biosynthesis of secondary metabolites in particular terpinoids, steroidal systems and alkaloids and some examples of biomedical relevance.</li></ul> On successful completion of the course students should be able to:  <ul><li>Draw and explain the structure and roles of nucleic and acids.  </li><li>Outline the processes involved in chemical synthesis of DNA.  </li><li>Discuss and explain the applications of DNA oligonucleotides.  </li><li>Define LogP, LogD, understand trends in potency, metabolism, solubility etc on drug development  </li><li>Describe key features involved in protein-ligand interactions, being able to identify side chain groups and their roles.  </li><li>Describe enzyme inhibition types, sketch equilibria, dose-response curves and outline tactics to increase potency.  </li><li>Describe how molecular modelling methods have evolved and integrate into modern, multidisciplinary structure-based design.  </li><li>Summarise the key concepts surrounding the potential energy surface, including methods of energy calculation and exploration, and appreciate the advantages and limitations of these methods  </li><li>Describe computer-based 2D and 3D approaches to drug design and discovery, including functional group mapping, virtual screening, de novo design, quantitative-structure activity relationships and database analysis.  </li><li>Compare and contrast 2D and 3D approaches computer-aided drug design, giving examples of their use in drug discovery projects.  </li><li>Describe the basic features of enzyme catalysis from a structural, functional and kinetic perspective.  </li><li>Be able to explain the key steps in several classical biosynthetic processes involving proteins and carbohydrates.  </li><li>Show and explain the steps involved in synthesis of cyclic monoterpenes terpenes from acetyl CoA through and be able to explain steps involved in selected higher terpene biosyntheses.  </li><li>Identify key steps and mechanisms, including stereoelectronic effects, in the biosynthesis of steroids  </li><li>Outline the steps involved in the synthesis of case examples of alkaloids, eg morphine and tropanes, and explain the role of PLP in amino acid biosynthesis.  </li></ul>Apply any of this knowledge to the process of drug discovery and development.   Students are expected to use material covered in lecture or tutorials to independently search different text sources to support their understanding and thus encourage and reinforce investigative skills. This will include direction to original literature sources as well as other web resources. Each section includes a dedicated workshop/exam review session and supporting worksheets are provided to help students develop problem-solving and analytical skills across a range of different sub-topics  Nucelic Acid Chemistry (Prof. Patrick Cai and Dr John Gardiner, weeks 4-7)<ul><li>Importance of nucleic acids in bioorganic chemistry (PC)</li><li>Structure of nucleic acids (PC)</li><li>Biosynthesis of nucleic acids (PC)</li><li>Chemical Synthesis of nucleic acids (JMG)</li><li>Recombinant DNA (PC)</li><li>Exam questions, tutorial and Q&A</li></ul>Computational chemistry and rational drug design Dr Richard Bryce (8 h)This part of the unit will introduce the student to molecular modelling and its role in the process of rational drug design, describing developments in molecular graphics and modelling; <ul><li>presenting the basis and limitations of calculations that underpin molecular modelling</li><li>introducing and discussing 2D and 3D automated hit identification and ligand design methods and illustrating these approaches using case studies.</li></ul>Enzyme Mechanisms and Secondary Metabolites (Dr J. M. Gardiner, weeks 9-12)<ul><li>Review of enzyme structure/reactivity from structure and functionality and enzyme mechanisms</li><li>Biosynthesis of acetylCoA and on to terpinoids and steroids</li><li>Alkaloid biosynthesis</li><li>Exam questions tutorial and Q&A</li></ul>Lectures will include revision/workshop elements during the lecture blocks with an exam revision at the end of each block.  Content is largely delivered through lectures. The material presented is fully supported by content on Blackboard. Tutorial problems are made available through Blackboard.  1 Written exam 100% Students have access to example problems/exam questions on Canvas and have the opportunity to review these with the lecturing staff for informal review and feedback during the course.Office hours will be advertised via Canvas and will run during the relevant lecture period.Students are advised to email staff to arrange meetings where possible during or outside of office hours. Two staff are based in MIB and one staff member is external to the department.   CHEM20412 Structure and reactivity of organic molecules Pre-Requisite Compulsory CHEM30411 Core Chemistry 1 Pre-Requisite Compulsory CHEM20411 Organic Synthesis Pre-Requisite Compulsory N <div><ul> <li>TDH Bugg, Introduction to Enzyme and Coenzyme Chemistry, Wiley, 3rd ed. 2012.</li> <li>J Mann, Chemical Aspects of Biosynthesis, OUP, 1994.</li> <li>GL Patrick, An Introduction to Medicinal Chemistry, 6th Ed. OUP, 2017</li> <li>G.Michael Blackburn, M.J. Gait, David Loakes, and D.M. Williams, Nucleic Acids in Chemistry and Biology, RSC, 3rd Ed, 2006.</li> <li>Free online nucleic acids book: https://www.atdbio.com/nucleic-acids-book</li> <li>The Handbook of Medicinal Chemistry: Principles and Practice. A David and SE Ward (Eds), RSC, 2015.</li></ul></div>  Assessment written exam 2 Lectures 18 Practical classes & workshops 6 0 74