Frontiers in Drug Development - Medicinal Chemistry 4 (SA)

Overview

STAFF

NAME CONTRIBUTION
Dr S. Cochrane
s.cochrane@qub.ac.uk
Module Co-ordinator. Antimicrobial Compounds and Targets (8 lectures and 1 revision class)
Dr G. Cotton - Head of Protein Therapeutics at Almac Discovery
graham.cotton@almacgroup.com
Antibody-Drug Conjugates (1 lecture).
Almac Discovery.
Dr C. O’Dowd
colin.odowd@almacgroup.com
& other Almac Discovery Staff An Industrial Perspective on Frontiers in Drug Development (3 Lectures)
Dr M McLaughlin
mark.mclaughlin@qub.ac.uk
Antibody-Drug Conjugates (5 lectures and 1 revision class).
Dr J. Vyle
j.vyle@qub.ac.uk
Nucleic Acid Drugs (8 Lectures and 1 revision class)
Dr P. Knipe p.knipe@qub.ac.uk
Late-Stage Functionalization (8 lectures and 1 workshop).

Antimicrobial Compounds and Targets (8 lectures and 1 revision class):
• 1.1. Introduction to antibiotics and antimicrobial resistance. Learn the key differences between prokaryotes and eukarotyes that allow for selectivity of antibiotics and the common categories of antimicrobial resistance.
• 1.2. Common cellular targets of antibiotics. Learn the major enzymes and biomolecules involved in cell-wall synthesis, protein synthesis, nucleic acid synthesis and the cell membrane. Understand the mechanisms by which these enzymes function.
• 1.3. Classical antibiotics. Learn the mechanism of action of several important classes of antibiotics, including fosfomycins, D-cycloserine, β-lactams, glycopeptides, antimicrobial peptides, macrolides, aminoglycosides, tetracyclines, chloramphenicol, ansamycins and fluoroquinolines. Resistance mechanisms against these classes of antibiotics will also be covered.
• 1.4. Methods to determine the mode and mechanism of action of a novel antimicrobial compound. Learn Key techniques used to determine the mode of action of antibiotics, including bactericidal kinetics assays and radiolabeled metabolite incorporation. Learn common methods used to identify mechanism of action, including cell morphology, in vitro enzyme assays, isothermal titration calorimetry, protein X-ray crystallography and membrane-disruption assays.
• 1.5. Rational design to overcome drug resistance. Learn the main strategies used to circumvent known anrimicrobial resistance mechanisms through case studies, including the generation of new β-lactams, β-lactamase inhibitors and the chemical synthesis of novel analogues of vancomycin, tunicamycin, erythromycin and acrylomycin.
• 1.6. Novel strategies to identify new antibiotics. Cover state-of-the-art methods used to uncover new antibiotic candidates, including novel bacterial-culturing techniques and genome-mining.

Nucleic Acid Drugs (6 Lectures and 1 revision class):
• 2.1. mRNA vaccines
• 2.2. Nucleic acid vaccine adjuvants
• 2.3. Identification of novel nucleic acid inhibitors through SELEX

Late-Stage Functionalization (8 lectures and 1 workshop):
• 3.1. Why Late-Stage Functionalization? Learn about the C-H bond as a functional group and the utility of LSF in the context of the drug discovery pipeline (probe development, pull-down experiments, lead optimization and ADME. Also cover practical considerations, including purification, analysis and high-throughput screening.
• 3.2. Guiding Principles in C-H Activation. Learn the concepts of innate vs guided C-H functionalizations and key factors in innate reactivity, including electronics (knowledge of nucleophilic and electrophilic positions of arenes, factors that stabilize radical intermediates etc.) and acidity (C-H functionalization by deprotonation). Guided reactivity classes, such as the concept of directing groups (high local concentration of reagent), steric control and molecular recognition. Understand methods to predict sites of C-H functionalization (e.g. DFT).
• 3.3. LSF of sp2 carbons exploiting innate reactivity. Regioselectivity in nucleophilic and electrophilic aromatic substitutions (and their radical analogues), recent advances relating to pyridines (e.g. McNally 4-functionalization of pyridines, Phipps’ Minisci chemistry, Fier method and borylation chemistry.
• 3.4. Directed approaches to LSF of sp2 carbons. Ortho-functionalization by directing groups (classical Pd C-H activation using e.g. 2-pyridines), meta-insertion using directing groups and molecular recognition (e.g. Phipps), steric control and recent vancomycin work (Miller, Pentelute).
• 3.5. C-H Functionalization of innately reactive sp3 carbons. H-abstraction/metal insertion at electron-rich C-H bonds (tertiary; adjacent to heteroatoms etc.) with subsequent C-X and C-C bond formation, deprotonation, e.g. lithiation-trapping of cyclic carbamates – e.g. Hodgson sparteine method; Seidel’s 2018 nucleophilic method, oxidation e.g. White’s Fe-(PDP) catalyst and carbene and nitrene insertions.
• 3.6. The Holy Grail: Directed C-H functionalization of sp3 carbons. A classical directed approach – the Hoffmann-Loffler-Freytag reaction; modern variants e.g. Yu ACIE 2017 306, specific directing groups, e.g. oximes (Chang JACS 2014), transient directing groups, e.g. work of Yu (JACS 2016 14554) and future perspectives on LSF.

Antibody-Drug Conjugates (6 lectures and 1 revision class):
• 4.1. Introduction to Antibodies. Learn what antibodies are, their structure (IgG), their therapeutic mechanisms and how they are produced and purified.
• 4.2. Key Concepts in Antibody-Drug Conjugates. Learn the key components of an antibody-drug conjugate, common methods to conjugate drugs to antibodies, common linkers used in ADCs and common payloads.
• 4.3. ADCs, a Look to the Future. Guest lecture by Dr. Graham Cotton from Almac Discovery on where the area is and where it’s heading.

An Industrial Perspective on Frontiers in Drug Development (4 Lectures):
• 5.1. Medicinal Chemistry in Action. Staff from Almac Discovery will cover cutting-edge topics including case studies on recent medicinal chemistry programmes and process development from a pharma perspective.

Learning Objectives

Medicinal chemists are responsible for the design of new molecules to treat disease, improving human health and prolonging life-expectancy. On completion of this module, you will have acquired advanced knowledge in the field of medicinal chemistry with an emphasis on cutting-edge methods in drug discovery and the synthesis of pharmaceutical agents. By the end of this course, you should be able to:
• Critically evaluate an antimicrobial compound, suggesting experiments to determine its mode/mechanism of action, relate its structure to possible resistance mechanisms and propose strategies to overcome such mechanisms.
• Contrast classical methods in antibiotic discovery with current state-of-the-art approaches.
• Describe the chemistry and biology associated with mRNA-based drugs and vaccines.
• Propose strategies to perform the late-stage functionalization of natural products/drug-lead candidates and suggest detailed mechanisms for the methods covered in this course.
• Understand the importance of antibodies as therapeutic agents, how they are produced and their structure.
• Know the key components of antibody-drug conjugates and mechanistic details of conjugation strategies, linkers and different types of drug payload.

Skills

Skills Associated With Module:
• Important skills will be gained on the critical evaluation of scientific methods and studies, the application of synthetic methods to novel structures and the ability to consider medicinal/biological problems from a chemistry perspective.
• Subject specific and problem-solving skills will also be gained, including the demonstration of self-direction, independent learning ability and originality in completion of practice problems.

Assessment

ASSESSMENT

Exam session 1st Semester
Assessment Profile
Element type Element weight (%)
Examination (3hrs) 100

Course Requirements:
• Lecture attendance
• Revision attendance
• Examination must be passed at 40 %.