Department of Chemistry Training 2015-16

BIOLOGICAL (BIO)

(BIO1) Protein Folding, Misfolding and Aggregation (8L)

AAN 1. Techniques to study protein structure and stability (Part II Recap) AAN 2. Techniques to study protein folding pathways (Part III Recap)

These first two lectures will be based on the undergraduate protein courses, and will provide a general introduction to the field. Contents will include protein structure determination (NMR, X-ray crystallography, CD, FRET), protein stability calculations (chemical / thermal denaturation) and the characterisation of protein folding pathways and mechanisms (stopped-flow, hydrogen exchange, -values).

AAN 3. Protein folding studies: simple systems AAN 4. Protein folding studies: more complex systems

These two lectures will go beyond the undergraduate course, to look at how it is possible to use a multidisciplinary approach to elucidate detailed mechanistic information about protein folding pathways. Contents will include the study of knotted proteins, characterisation of misfolded proteins, the use of optical tweezers and AFM, the study of co-translational folding, and the identification of cooperativity in multidomain proteins.

SEJ 5. Molecular chaperones: role in biological protein folding and misfolding SEJ 6. Molecular chaperones: therapeutic targets or therapeutic agents?

These two lectures will start by discussing the important differences between protein folding in vitro and protein folding in vivo, and will highlight the need for biological chaperones and the consequences of chaperone disfunction. Contents will include details of ATP-independent chaperones, such as the heat shock proteins and the ATP-dependent chaperones, such as the GroEL/GroES complex. The lectures will finish by looking at the suppression of protein aggregation by natural chaperones and will discuss the possible therapeutic uses of this discovery.

SLS 7. Intrinsically disordered proteins: structure and function SLS 8. Studying the coupled folding and binding of IDPS

These final two lectures will look at a class of proteins that are natively unstructured but biologically active and thus appear to break the structure-function paradigm. Such proteins are not anomalies and indeed recent studies suggest that over 1/3 of proteins in eukaryotic organisms contain intrinsically disordered regions. These lectures will look at the possible reasons for disorder and will suggest why many such proteins are found to be signaling hubs. The course will finish by looking at techniques that can be used to study coupled folding and binding of these proteins and will emphasise the common flaws and misconceptions that hinder such kinetic studies.

BIOLOGICAL (BIO)

(BIO2) Biosynthesis and its Manipulation (2L)

This two part lecture series aims to give an overview of the biosynthesis of the major natural product classes – the terpenoids, polyketides, alkaloids and ribosomal/non-ribosomal peptides. The end of the second lecture will feature a discussion of the genetic manipulation of natural product producing organisms to generate new unnatural analogues, with industrially successful examples of this exciting new technology show-cased.

BIOPHYSICAL TECHNIQUES: THEORY & PRACTICAL APPLICATIONS (BT)

This is a series of talks and a symposium, created at and hosted by the MRC-LMB, outlining the theory and practical applications of various biophysical techniques as applied in structural biology research. Topics ranging from mass spectrometry to bioinformatics, flow cytometry to light scattering techniques will be covered: the detailed schedule will be sent out once it is finalised. Signing up is not required (just turn up) but you should keep a record in your Graduate Student Training Log Book of which sessions you have attended to add to those which you have signed up for electronically.

CATALYSIS (CA)

(CA1) New Directions in Metal and Non-Metal Catalysis (3L)

Topics: frustrated Lewis Pairs; non-transition metal catalysis; activation of small molecules using lattices.

The course involves the applications of non-transition metals in catalysis and molecular activation. The two main areas to be discussed are:

a) The concept of frustrated Lewis pairs (FLPs) in small molecule activation and, in particular, hydrogen splitting. b) The applications of main group elements in various bond-forming reactions (dehydrocoupling, hydroamination etc).

The applications of these areas in synthetic transformations and in energy storage will be major themes.

CATALYSIS (CA)

(CA2) Metal Catalysis in Evolved Systems (3L)

How to handle dioxygen without oxidising yourself.

PLEASE NOTE THAT LECTURE 2 ON 15 APRIL HAS BEEN CANCELLED

Lecture 1 – Strategies for generating iron oxy species for CH bond oxidation This lecture will look at how mononuclear and dinuclear iron sites can generate iron superoxy, peroxy and oxo species for insertion of O into CH bonds and related activities. It will include a comparison of the activity of the best of synthetic catalysts with what is known about the hugely abundant natural ones.

Lecture 2 – The Cytochrome P450 paradigm Cytochromes P450 are a special case of monooxygenases that are widespread across biological systems, and especially important to pharmaceutical companies as modifiers of drugs. The protein engineering of P450s will be discussed.

Lecture 3 – Water splitting and O2 generation How are 4 oxidising equivalents brought together at the OEC in Photosystem II and what is the current state of mimicking this centre?

CATALYSIS (CA)

(CA3) Thermodynamics and Kinetics in Catalysis (2L)

(please note that this course was due to be held on 16 and 18 February 2015)

Good knowledge of kinetics and thermodynamics is often required for the elucidation of catalytic reaction mechanisms. While a catalyst does not alter the overall thermodynamics of a catalysed reaction, equilibrium reactions may still be part of the catalytic cycle. In this course we will look first briefly at the role of the catalyst with respect to kinetics and thermodynamics, before investigating methods and techniques used to gain insight into catalytic reaction mechanisms. Finally, some examples from literature will be highlighted where kinetic and thermodynamic investigations played a crucial role in the elucidation of the reaction mechanism and led to significant improvement of this catalytic reaction.

CATALYSIS (CA)

(CA4) Organocatalysis (2L)

Organocatalysis is a field of asymmetric catalysis that uses small organic molecules to catalyse organic transformations. Although sporadic reports of small organic catalysts have been documented in the literature for decades, it was not until the late 1990's that organocatalysis became recognised as the third major branch of asymmetric catalysis, complementing transition metal and enzymatic catalysis. The first lecture will highlight the areas enamine and iminium catalysis followed by a lecture focusing on broader activation themes, including hydrogen bonding, NHC, and phase transfer catalysis. Together the lectures will outline key organocatalytic transformations with emphasis on mechanistic understanding and how the field developed.

CATALYSIS (CA)

(CA5) Sustainability of Catalytic Chemical Processes: Technical and Environmental Aspects (2L)

During the two lectures we will examine the concept of sustainability and its implications for catalytic chemistry and processes. We will learn how to quantify sustainability to be able to argue for adoption of new catalytic processes and we will examine how development of one part of the overall process, i.e. new catalyst, impacts on the rest - feedstocks, separations etc. Several examples of novel reactor technology and novel catalytic systems will be examined in terms of their claims for sustainability. Finally, we shall develop a system-level approach to design of catalytic processes.

Table of Contents 1. The concept of sustainability 2. Sustainability frameworks 3. Sustainability metrics 4. Catalytic process as part of an integrated system 5. Examples of new catalysts in new processes - are new processes more sustainable? 6. Do not optimise one part of your process! 7. System-level understanding of catalytic processes: from molecular fundamentals to sustainability.

CATALYSIS (CA)

(CA6) Asymmetric Homogeneous Hydrogenation in the Synthesis of APIs (1L)

Course Presenter: Dr Antonio Zanotti-Gerosa (Johnson Matthey)

Homogeneous hydrogenation and transfer hydrogenation are recognised as powerful tools for the industrial production of chiral intermediates. The talk, much based on the personal experience of the author, will provide a brief overview of the historical development of this area, a discussion on the scope and limitations of the technology and its complementarity with other technologies (e.g. biocatalysis, heterogeneous catalysis), a discussion on the key parameters affecting the economic viability of industrial asymmetric hydrogenation processes and an outlook on future research directions. Several case studies of projects developed by Johnson Matthey, Catalysis and Chiral Technologies with industrial customers will be reported.

CATALYSIS (CA)

(CA7) Sorption In Porous Media (3L)

Porous materials are widely used in catalysis. Capillary condensation of various gases is used for structural characterisation of porous materials in terms of porosity, internal surface area and distribution of the pore sizes. In these lectures, we consider mechanisms of capillary condensation and discuss such physical phenomena as hysteresis, avalanches and continuous/discontinuous phase transitions. The emphasis is made on the theoretical approaches used for description of condensation in confined space.

CATALYSIS (CA)

(CA8) Surface Chemistry and Heterogeneous Catalysis (2L)

These lectures will introduce both the fundamental processes that govern chemistry at solid surfaces and the techniques available for studying these processes in detail. The relationship between surface chemistry and heterogeneous catalysis will be discussed, with particular emphasis on the different conditions encountered in real-world systems versus the highly simplified model systems studied in the laboratory.

CATALYSIS

(CA9) Modelling of Heterogeneous High Temperature Chemical Reactions on Catalytic Surfaces (2L/W)

Lecture type: Practical along with some theory slides - lectures will be conducted in a computer suite running the software kinetics.

Summary: In the lectures, we shall introduce a mathematical model for heterogeneous reactions of gas-phase species on a catalytic surface. As a practical example, we shall study the Fischer-Tropsch synthesis of straight chain hydrocarbons on a Co/g-Al2O3 catalyst using a mechanism describing the hydrogen-assisted CO activation of the catalyst. The reacting system is simulated using the kineticsTM software package to solve the underlying mathematical equations and to perform parameter studies of the problem.

DRUG DISCOVERY (DD) (I)

(DD1) The Drug Discovery Process (2L)

Drug discovery is a complex multidisciplinary process with chemistry as the core discipline. A small molecule New Chemical Entity (NCE) (80% of drugs marketed) has had its genesis in the mind of a chemist. A successful drug is not only biologically active (the easy bit), but is also therapeutically effective in the clinic – it has the correct pharmacokinetics, lack of toxicity, is stable and synthesisable in bulk, selective and can be patented. Increasingly, it must act at a genetically defined sub-population of patients. Medicinal chemists therefore work at the centre of a web of disciplines – biology, pharmacology, molecular biology, toxicology, materials science, intellectual property and medicine. This fascinating interplay of disciplines is the intellectual space within which a chemist has to make the key compound that will become an effective medicine. It happens rarely, despite enormous investment in time, money and effort. What factors make a program successful? I would like to briefly outline the process, but importantly to offer some key with examples of success.

DRUG DISCOVERY (DD) (I)

(DD2) Agrochemical Discovery

Course presented by Dr Steve Smith (Syngenta)

As the world population continues to grow, so does the need to increase global food production sustainably with limited resources. Agrochemicals, in the form of herbicides, fungicides and insecticides, provide an important tool for farmers to combat the weeds, fungi and insect pests that target their crops and help to ensure reliable yields and quality produce. Resistance, emerging pests, abiotic stress and regulatory pressure all drive an ongoing search for new and more innovative crop protection products. This lecture will outline the process used to discover new agrochemicals, from lead generation through to development. It will show the critical roles that chemistry, biology and human & environmental safety play, illustrated with a number of recent examples.

DRUG DISCOVERY (DD) (I)

(DD3) Targeted Anti-Cancer Therapeutics (2L)

The targeted delivery of effector molecules into diseased tissues has emerged as a promising strategy for the treatment of cancer and other serious conditions. Linking a therapeutic effector (e.g. cytotoxics, proinflammatory cytokines or radionuclides) to a ligand specific to a marker of disease results in preferential accumulation of the effector molecule at the target tissue. This offers the double benefit of increased effective concentrations at the intended site of action and low concentrations in healthy tissues, thus reducing side effects. In the course of these two lectures we will discuss strategies for the discovery of selective ligands against markers of disease, conjugation chemistry in the context of drug-delivery strategies, and examples of recently approved FDA drug conjugates for the treatment of cancer.

DRUG DISCOVERY (DD) (I)

(DD4) Fragment-based Drug Discovery (2L)

Fragment-based approaches to finding novel small molecules that bind to proteins are now firmly established in drug discovery and chemical biology. Initially developed primarily in a few centres in the biotech and pharma industry, this methodology has now been adopted widely in both the pharmaceutical industry and academia. After the initial success with kinase targets, the versatility of this approach has now expanded to a broad range of different protein classes such as metalloproteins and protein-protein interactions. In the course of these two lectures we will explore the different strategies for finding a fragment hit and the subsequent elaboration strategies used in order to increase potency to develop a lead compound.

DRUG DISCOVERY (DD) (I)

(DD5) Computational Approaches to Chemical Biology and Medicinal Chemistry (1L + 2W)

In this lecture and practical, Dr Bender will show how chemical and biological data can be used on the one hand to understand the bioactivity of drugs in living systems, and on the other hand how computers can be used to design novel bioactive compounds. This will cover both examples from the current research in his group, together with academia and pharmaceutical industry, as well as more fundamental aspects from the cheminformatics area which will be used in a computational drug discovery practical afterwards.

DRUG DISCOVERY (DD) (I)

(DD6) Process Chemistry (2L)

In these two complementary lectures, between which lunch will be provided for all participants, industry experts on process chemistry from GSK and Syngenta will share their experiences and challenges gathered over many years of experience.

Lecture 1: A GSK Case Study (1L) Dr Richard Horan

As potential new drugs approach launch there is an ever-increasing application of the tools of process chemistry (statistical experimental design, reaction kinetics, in-situ reaction monitoring etc) in order to define a control strategy that provides a thoroughly understood, robust reaction sequence that can be used to manufacture the drug to acceptable quality on an ongoing basis. This control strategy also forms a key part of any regulatory submission required before the drug can be sold. This lecture will present a recent case study on the process development carried out on a real GSK drug molecule and demonstrate the tools and approaches employed as the control strategy evolved.

Recommended text: Lee, S. and Robinson, G. Process Development: Fine Chemicals from Grams to Kilograms (Oxford Chemistry Primers); OUP: Oxford, 1995.

Lecture 2: What Influences a Reaction? Dr George Hodges (Syngenta)

Scale up is made complex by the fact that some parameters change while others remain constant. Successful scale up therefore requires an understanding of the reaction “driving force” and how it changes as a function of scale. This talk will go through building up a fundamental understanding of a reaction from both a chemical and engineering point of view and show how this can not only help in scaling-up, but can also be used to influence lab scale reactions in ways usually ignored.

Recommended text: Atherton, J. and Carpenter, K., Process Development - Physicochemical Concepts (Oxford Chemistry Primers) ; OUP: Oxford, 2000.

INTRODUCTORY LECTURES (IL)

(IL1) You and Your PhD: How to Write a Thesis

In this introductory session, time will be devoted to a discussion of how to plan your time effectively on a day to day basis, how to produce a dissertation/thesis and the essential requirements of an experimental section. General information will also be provided on the regulations and process surrounding submission of the first year probationary report and PhD thesis.

NOVEL MATERIALS AND MICRODROPLETS (MM)

(MM1) From Molecules to Materials (3L)

The increasing need to develop low-temperature ‘soft’ approaches to existing or brand new materials presents the synthetic chemist with challenging and fresh horizons in the future. This short course will highlight how even simple inorganic and organic molecules, which have the right stoichiometry and characteristics, can be used to make electronic, catalytic and energy materials in a ‘bottom-up’ approach. The primary focus of the course is on the synthesis and design of precursors and the various epitaxial (vapour-phase) and solution approaches that have been used to deposit materials, comparing these approaches to high-temperature solid-state synthesis in particular. It will also describe how the array of modern solid-state methods can be used to characterise materials and how these materials function on a qualitative level in a number of key applications.

NOVEL MATERIALS AND MICRODROPLETS (MM)

(MM2) Conjugated polymers: Synthesis, Devices and Research Challenges (2L)

Course Presented by Cambridge Display Technology

The first of the lectures in this section will cover polymer organic light emitting diode materials and the new and exciting challenges these pose for synthetic organic chemists. The second will consider the route from organic materials synthesis to high performance solution processable electro-optical devices.

NOVEL MATERIALS AND MICRODROPLETS (MM)

(MM3) Artificial and Natural Materials: Properties, Manufacturing and Applications (3L)

Nano-structured materials interact with light in unconventional ways: For example, it is possible to create brilliant and iridescent coloration using transparent materials or make invisibility cloaks using metals. Within this course, I will provide an overview on how light-propagation can be manipulated and tailored by nano-structuring materials. In particular, the first lecture will revise the basic principles of light-matter interaction and photonic crystals. The second lecture will focus on fabrication techniques and unresolved challenges for manufacturing of such materials on a large scale. In the last lecture, I will show how nature produces extremely complicated photonic structures (sometimes impossible to replicate artificially) on large-scale at room temperature using only simple materials like cellulose or chitin.

NOVEL MATERIALS AND MICRODROPLETS (MM)

(MM4) Microdroplets: Tiny Lab Toys with Enormous Potential (2L)

Physical behaviour of fluids when confined in micro sized cavities is quite different than the behaviour of fluids in the macro-scale world. In the last decade, a better understanding of microfluidics boosted the development of this specific area of knowledge. In these lectures we will go through the physical basics from microfluidics to microdroplets, the design and fabrication of microfluidic devices for microdroplet generation and manipulation, as well as into the range of applications that this novel technology can cover.

NOVEL MATERIALS AND MICRODROPLETS (MM)

(MM5) Plasmonic Nanoparticles and Sensing Applications Based on Surface-Enhanced Raman Scattering (SERS) (2L)

Nowadays, nanotechnology is one of the most important areas of current research, due to the unique optical properties that plasmonic nanoparticles can possess. A fine control of the size, shape and composition of such nanoparticles allows the scientists to develop a broad range of applications based on these materials. These lectures will be focused on the synthesis and development of nanomaterials and their use in combination with surface-enhanced Raman scattering (SERS). SERS is an analytical technique that takes advantage of the specific optical properties of nanoparticles. Specifically, SERS spectroscopy has been applied in biosensing, environmental analyses, forensic science, chemical war agent detection and art.

SOUND BITES (SB)

(SB1) Modelling Atmospheric Chemistry (1L)

Understanding how future changes in climate and emissions will affect the composition of the atmosphere requires the use of numerical models of transport and chemistry. In this lecture I will give an overview of the history of modelling atmospheric composition and review the fundamental components of atmospheric chemistry models.