Introduction to Drug Design and Development

Introduction to Drug Development

Introduction to drug development

• Drug development (aka drug discovery) has been key to combating
  diseases & health-related issues
• Crucial advancements came in the mid-19th century, but the 20th
  century set most significant advances & understanding of scientific
  principles, specifically chemistry & biological concepts being vital for
  drug development

Chemistry and Biology in Drug Development

Chemistry:
Key to preparation of drug
molecules
Biology:
Key to providing assays for
testing therapeutic potential

• Modern advances have largely been supported by the rise in the
  pharmaceutical industry
• Natural products is still a major significant focus as a source of new
  drugs, thereafter following on with derivatives by synthetic
  manipulation

Drug Development Overview

Drug development involves
a number of specialities or
disciplines, and concepts
brought together for
producing that single
compound that can change
patients' circumstances

Key Disciplines in Drug Development

Structure
& Biophysics
Sample
Management
Medicinal
Chemistry
Screening
Science
Computational
Science
Reagents
Statistics
Assay
Development
Adapted from: JP Hughes, S Rees, SB
Kalindjian and KL Philpott, British Journal of
Pharmacology (2011) 162 1239

Drug Origins

V, 101, 6%
B, 250, 16%
S*/NM, 162, 10%
N, 67, 4%
S*, 61, 4%
NB, 9, 1%
S/NM, 172,11%
IND, 320, 21%
S, 420, 27%
BON MNB UND
S/NM
S* S*/NM
Natural products include
marine & microbial sources
Natural Products as Sources of New Drugs
from 1981 to 2014, Newman et al., J. Nat.
Prod., 2016, 79, 629.
V
B
N
NB
ND
S
S*
S* /NM
Biological macromolecule
Unaltered natural product
Botanical drug (defined mixture)
Natural product derivative
Synthetic drug
Synthetic drug (NP pharmacophore)
Mimic of natural product
Vaccine

Agonists, Antagonists and Inverse Agonists

Drug molecules often induce their therapeutic effect by being one of the
following:

Types of Drug Molecules

Agonist:
A chemical that binds to a receptor and activates the
receptor to produce a biological response
Antagonist:
A chemical that binds to a receptor and blocks the action of
the agonist
Inverse agonist:
A chemical that binds to a receptor and induces a
pharmacological response opposite to that of the agonist

The Renin-Angiotensin-Aldosterone System (RAAS)

Angiotensinogen
(polypeptide secreted by the liver)
Renin
Renin Inhibitors
X
(enzyme secreted by the liver;
converts angiotensinogen to
angiotensin I)
Angiotensin Converting Enzyme
[ACE]
ACE Inhibitors
X
(secreted by lungs; ACE
converts angiotensin I to
angiotensin II)
Angiotensin
receptor
blockers (ARBs)
X
Angiotensin II Receptors
(located in smooth muscle,
heart, adrenal glands, brain)
INCREASED BLOOD PRESSURE
(HYPERTENSION)

Approaches to Discover an Active Compound

2 approaches:

Serendipity in Drug Discovery

Serendipity:
Chance discovery by screening
all available drug-like
compounds from all sources
(natural or synthetic) for
biological activity against all
targets using appropriate
biological assays & High
Throughput techniques

Ligand/Structure Based Design

Ligand/Structure based design:
Drug design based on modification
of natural ligands of the drug
targets, e.g., receptor ligand (agonist
/ antagonist), enzyme substrate or
natural inhibitor (often computer
aided, aka CADD)

Phenotypic Drug Discovery (PDD)

Phenotypic Drug
Discovery (PDD)
... searching for a compound that causes an
observable physical change in a whole
biological system mimicking the disease,
e.g., animals or cells

Target Directed Discovery (TDD)

Target Directed
Discovery (TDD)
... searching for a compound that binds with a
target known to cause an observable physical
change in the biological system

Approaches to Discover an Active Compound

• A specific protein/RNA molecule etc
  that a drug molecule interacts with

Target Validation and Assay Development

Target
validation
Assay
development
Screening
Hits &
leads

Phenotypic Drug Discovery vs. Target Directed Discovery

Phenotypic Drug
Discovery (PDD)
Target
Target Directed
Discovery (TDD)
Assay
development
Screening
Hits &
leads
Target
validation

• Targets known (modern approach, mostly used)
• Typically use recombinant proteins or cells over-
  expressing the target of interest
• Assay throughput is usually high
• Screens used are to measure a compound's
  effect on the target of interest
• Need to confirm compound effects in a relevant
  biological assay
• Targets are unknown (mostly historic approach, pre-1980s)
• Ideally use native human cells
• Assay throughput is usually low
• Screens used to measure the desired biological effect in cells, tissues or whole organisms
• Multiple, biologically relevant targets & pathways are simultaneously interrogated
• Need to do target deconvolution to identify target

Screening for an Active Compound

Screening

Options for Screening

Options for screening (can be used in parallel or in isolation):

• Molecular modelling
• High-throughput screening (HTS) (mostly for TDD)
• Fragment screening (can involve crystallography expertise)
• Knowledge-based design (medicinal and computational expertise
  and using existing published patents and literature)

Drug Targets and Target Validation

Target
validation

Points to Note on Drug Targets

Points to note:

• Some drugs have more than one target site (e.g., ion channel drugs).
• There are subtypes of many known targets
• A drug may target/interact with one or more target subtypes
• Understanding that a gene encodes each protein enables different
  avenues to be explored to find new drug targets
• Target validation (especially for new targets) aims to gather detailed
  information on therapeutic efficacy & safety limits
• Good target identification & validation increases confidence in the
  relationship between target & disease
• Target deconvolution is the retrospective identification of molecular
  targets that underlie observed phenotypic responses; this is
  important for elucidating biological mechanisms of disease & aids
  rational drug design/increases efficiency

Phenotypic Drug Discovery Poll

Join: vevox.app ID: 150-052-946
POLL OPEN
Phenotypic drug discovery ...

1. starts with a known drug target
   6.25%
2. requires target deconvolution
   14.58%
3. uses specialised over-expressing cells
   2.08%
4. uses high throughput assays
   8.33%
5. is used when the target is unknown
   68.75%

Drug Discovery Process

The 'drug discovery' process involves:

• Discovery and understanding
  properties of drug targets for
  selectivity
• Identifying suitable bioassays
• Sources of lead compounds
• Techniques for isolation
• Structure determination and
  purification
• Optimising target interaction
  (structure-activity relationships,
  SARs)
• Clinical trials (various stages)
• Approvals and marketing of the drug
  for patient use

Drug Discovery Process Steps

Drug discovery process
10,000-20,000 candidate drugs
Step 1
Discovery & screening
High throughput screening / target
validation
Step 2
Lead optimisation
Step 3
ADMET
Adsorption, distribution,
metabolism, excretion, toxicity
Step 4
Clinical trials
Step 5
MHRA approval
Medicines and Healthcare
products Regulatory Agency
1 drug to
market

Pharmaceutical Development Process Costs and Timescales

Pharmaceutical development process
£1150M
£436M
£97M
£177M
£206M
£184M
£50M
Drug Discovery
Testing
Phase 1 Trial
Phase 2 Trial<](https://www.pharmaceutical-journal.com/news-and-analysis/features/the-cost-of-developing-a-new-drug/20068196.article)
Phase 3 Trial
Approval
Target identification
Target validation
Lead identification
Lead optimisation
4 year
1.5 years
1.5 years
1.5 years
2.5 years
1.5 years
12.5 years
(all costs and timescales are averages between UK pharmaceutical companies)
Source: The Pharmaceutical Journal, PJ March 2015 online, online | URI: 20068196
https://commons.wikimedia.org/wiki/File:The Pharmaceutical Development Process.png

Combinatorial Synthesis

• This approach makes large numbers of compounds (potential drug
  candidates) quickly & in parallel by combining building blocks in
  different sequences, that can then be tested for drug efficacy
• The sequences (AB, CC etc) can then be tested for efficacy.
• Example 1:
  B1,B2,B3
  (diff R2 groups)
  R2
  O
  H2N
  O
  O
  R1
  R2
  R4-NH2
  R1
  R2
  0
  R3
  R1
  H
  H
  :0
  0
  O
  -
  R3
  R4
  A-B-C
  (diff R1,R2,R4 groups)
  A1,A2,A3
  (diff R1 groups)
  C1,C2,C3
  (diff R4 groups)
  polyamide
  Ò
  CI
  HNA
  B
  C
  A1
  B1
  C1
  A1-B1-C1
  C2
  A1-B1-C2
  C3
  A1-B1-C3
  B2
  C1
  A1-B2-C1
  C2
  A1-B2-C2
  C3
  A1-B2-C3
  B3
  C1
  A1-B3-C1
  C2
  A1-B3-C2
  C3
  A1-B3-C3
  A
  B
  C
  A2
  B1
  C1
  A2-B1-C1
  C2
  A2-B1-C2
  C3
  A2-B1-C3
  B2
  C1
  A2-B2-C1
  C2
  A2-B2-C2
  C3
  A2-B2-C3
  B3
  C1
  A2-B3-C1
  C2
  A2-B3-C2
  C3
  A2-B3-C3
  A
  B
  C
  A3
  B1
  C1
  A3-B1-C1
  C2
  A3-B1-C2
  C3
  A3-B1-C3
  B2
  C1
  A3-B2-C1
  C2
  A3-B2-C2
  C3
  A3-B2-C3
  B3
  C1
  A3-B3-C1
  C2
  A3-B3-C2
  C3
  A3-B3-C3
  27 compounds made, which
  can be tested for drug efficacy

Combinatorial Synthesis Example 2

• Example 2: amino acids to make a polypeptide (initially linked to a
  polystyrene bead, with later is removed):
  Resin (polystyrene beads)
  A
  + B
  +
  A
  B
  C
  A
  B
  C
  A
  B
  C
  +
  A
  + B
  +
  C
  A
  A
  A
  B
  A
  C
  B
  A
  B
  B
  B
  C
  C
  A
  c
  B
  C
  c
  1. Split resin into reactors A, B, and C
  2. Couple building blocks A, B, and C
  3. Pool and mix resin
  4. Split and react again with A, B, and C
  Obtain a library of fully
  permuted compounds from
  the combinations of A, B, and C
  A, B, C are amino acids
  C
  +

Advantages of Combinatorial Synthesis

Combinatorial
synthesis
Advantages of a combinatorial approach:

• Create a large range of molecules that can be
  screened effectively
• Increase probability of finding a compound with the
  desired therapeutic properties
• Process can be robotised for efficiency

High Throughput Screening (HTS)

• HTS is used for identifying lead compounds that have therapeutic potential with minimal side effects
• Large numbers of compounds are screened in a number of bioassays, often disease focused
• HTS often linked to combinatorial synthesis of compounds.
• Initial primary screening identifies potential bioactive compounds
• Then, secondary screening then used to confirm the activity, check specificity and compare potency
• Potential compounds are then examined as a hit-to-lead process, identifying common structural features
  (structure-activity relationships, SARs)
• Lead optimisation (reducing side-effects/improve specificity & potency), clinical trials (monitoring
  ADMET) then follows, assisted by computational modelling and biochemical/cell-based assays & in vivo
  models.

Target-Directed Drug Discovery Process Poll

Join: vevox.app ID: 150-052-946
POLL OPEN
Which is least likely to feature in the early stages
of the target-directed drug discovery process?

1. lead optimisation
   15.15%
2. screening
   18.18%
3. clinical trials
   30.3%
4. target validation
   24.24%
5. assay development
   12.12%