WEEK 1: DRUG DISCOVERY, Part II

 Drug discovery: intersection of synthetic organic chemistry

(medicinal chemistry), molecular & structural biology, and
pharmacology

 Drug development: discovery, hit to lead, lead optimisation,

process development

Week 1 School of Chemical Engineering Life Impact The University of Adelaide

 LECTURER
Prof. Volker Hessel
Room: N210, Engineering North
Email: volker.hessel@adelaide.edu.au
Student Consulting Period: Friday 15:30 - 17:30 am

Literature
1) Drug discovery: J. P. Hughes, S. Rees, S. B. Kalindjian, K. L. Philpott, Br J Pharmacol.
162, 6 (2011) 1239–1249; J. Eder, R. Sedrani, C. Wiesmann Nature Reviews Drug
Discovery 13 (2014) 577–587
2) Drug development: P. Muntha RRJPPS 5, 1 (2016) 135-142
3) High-throughput screening: R. Macarron, M. N. Banks, D. Bojanic, D. J. Burns, D. A.
Cirovic, T. Garyantes, D. V. S. Green, R. P. Hertzberg, W. P. Janzen, J. W. Paslay, U.
Schopfer, G. S. Sittampalam Nature Reviews Drug Discovery 10 (2011) 188–195
4) Bioassays: S. J. Panuganti RRJOB 3, 2 (2015) 1- 13;
https://www.slideshare.net/Sindhukuberappa/bioassay-techniques
5) Clinical development: https://www.australianclinicaltrials.gov.au/what-clinical-trial/phases-
clinical-trials; https://medicinesaustralia.com.au/policy/clinical-trials/;
https://www.fda.gov/forpatients/approvals/drugs/ucm405622.htm

Week 1 School of Chemical Engineering Life Impact The University of Adelaide Slide 2
 Learning outcomes
 Get to know drugs
Definition, classification, most expensive/most prescribed/etc., AUS statistics

 Drug delevopment
Stages, success, timelines, costs, time

 Drug discovery
Stages, classical vs. reverse pharmacology, high-throughput screening, assays,
rational drug design

 ‘Must-haves’
Affinity/efficacy/potency, selectivity, metabolic stability, non-toxicity, bioavailability

 Hit to lead & Lead optimisation

H2L & LO steps and targets

 Clinical development
Preclinical & clinical steps and targets
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 ASSAY AND ITS TYPES

Investigative (analytic) procedure for measuring the presence, amount, or

functional activity of a target entity (the analyte)
Analyte: drug, a biochemical substance, or a cell in an organism or organic sample
 Sample processing and manipulation
 Discrimination/identification/detection system
 Target-specific DISCRIMINATION/IDENTIFICATION principle
 Signal (or target) AMPLIFICATION system
 Signal DETECTION (and interpretation) system

Bioassay: response is biological activity of living objects; in vivo, whole organism, ex vivo
body part, ex vivo organ, ex vivo part of an organ, tissue, cell
Ligand binding assay: response is a ligand binding a receptor (usually a large protein)
Immunoassay: response is an antigen antibody binding type reaction

Amplification
Enzyme assay; Light detection systems; Radioisotope labeled substrates; Polymerase
Chain Reaction Assays; Combination Methods

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 ELISA

Enzyme-linked immunosorbent assay

 Quantitative analytical method that measures absorbance of color

change from antigen-antibody reaction
 ELISA is used to measure variety of substances in human body from
cortisol levels for stress to glucose level for diabetes

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 RATIONAL DRUG DESIGN

Inventive process of finding new medications

by knowledge of a biological target

 Basic case: design of molecules that are complementary in shape and charge
to the biomolecular target
 Computer-aided drug design: use of modelling = molecular mechanics, semi-
empirical, ab initio quantum chemistry methods, or density functional theory
 Structure-based drug design: knowledge of the three-dimensional structure of
the biomolecular target
Ligand-based drug design + structure-based drug design

In addition to small molecules, biopharmaceuticals including peptides and especially

therapeutic antibodies are investigated as drugs

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  Must-Haves
Affinity/efficacy/potency, selectivity, metabolic
stability, non-toxicity, bioavailability

Week 1 School of Chemical Engineering Life Impact The University of Adelaide

 MUST-HAVE PROPERTIES FOR A DRUG

 Affinity

 Efficacy/potency

 Selectivity to reduce the potential of side effects

 Metabolic stability to increase the half-life

 Non-toxicity

 Bioavailability

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 POTENCY, AFFINITY, EFFICACY

 Potency/EC50: measure of drug activity expressed in terms of the amount

required to produce an effect of given intensity
A highly potent drug (fentanyl, alprazolam, risperidone) evokes a given response at low con-
centrations, while a drug of lower potency (codeine, diazepam, ziprasidone) evokes the same
response only at higher concentrations. The potency depends on both the affinity and efficacy.

 Affinity: measure of the ability of the drug to bind to its molecular target
Fast/strong binding = higher affinity

 Efficacy/Intrinsic Activity: relative ability of a drug-receptor complex to

initiate a response at the molecular, cellular, tissue or system level

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 EFFICACY

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 POTENCY

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 DRUG SELECTIVITY

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 DRUG METABOLISM

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 METABOLIC PATHWAYS

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 DRUG SAFETY

Pharmacovigilance (PV), also known as drug safety

Collection, detection, assessment, monitoring, and prevention of adverse effects
with pharmaceutical products
 Adverse event (AE) reporting involves the receipt, triage, data entering,
assessment, distribution, reporting (if appropriate), and archiving of AE data
and documentation
Hospital Casemix Protocol (HCP)
The HCP data set is a valuable source of
information for the private health industry.

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 DRUG BIOAVAILABILITY

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 INCREASE OF DRUG
BIOAVAILABILITY

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  Hit to Lead &
Lead Optimisation
H2L & LO steps and targets

Week 1 School of Chemical Engineering Life Impact The University of Adelaide

 HIT TO LEAD & LEAD OPTIMIZATION

Hit to Lead (H2L; lead generation)

Stage in early drug discovery where hits from HTS are evaluated and undergo
limited optimization to identify promising lead compounds
Hit confirmation and hit expansion
 From micromolar 10−6 molar concentration range to nanomolar (10−9 M) range
 Limited optimization to improve metabolic half life: test animal models
 Improve selectivity against other biological targets with undesirable side effects

Lead optimization (LO)

New analogs with improved potency, reduced off-target activities, and physio-
chemical/metabolic properties
Chemical modification of the hit structure, employing knowledge of the
structure-activity relationship (SAR)
Experimental testing based on animal efficacy models and ADMET (in vitro
and in situ) ADME-Tox, absorption, distribution, metabolism, and excretion

Target identification and target validation

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 Clinical Development
Preclinical & clinical steps and targets

Week 1 School of Chemical Engineering Life Impact The University of Adelaide

 CLINICAL DEVELOPMENT
Preclinical phase
New chemical entities (NCEs) from drug discovery
 Access safety, toxicity, pharmacokinetics, and metabolism of this NCE in humans
 Dose and schedule for the first use in a human clinical trial ("first-in-man" [FIM])
 Physicochemical properties of the NCE: chemical makeup, stability, and solubility
 Optimize the process - scale up from a medicinal chemist producing milligrams,
to manufacturing on the kilogram and ton scale
 Suitability to package as capsules, tablets, aerosol, intramuscular injectable,
subcutaneous injectable, or intravenous formulations

Clinical phase
 Phase I trials: healthy volunteers, determine safety and dosing
 Phase II trials: initial reading of efficacy and further explore safety in small
numbers of patients having the disease targeted by the NCE
 Phase III trials: large, pivotal trials to determine safety and efficacy in
sufficiently large numbers of patients with the targeted disease
 Phase IV trials: post-approval trials, sometimes a condition attached by FDA

Week 1 School of Chemical Engineering Life Impact The University of Adelaide