Drug Design II

PHAR2821 - 2016
Protein Structures
Drug Receptor Interactions
Intro to Drug Design WSs
Presented by
A/Prof Thomas Balle
Faculty of Pharmacy

The University of Sydney Page 1

 Learning Objectives

– Proteins and protein structure

– The most common macromolecular drug targets
– Drug-receptor interactions

– Intro to DD2 and DD3 workshops

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LEARNING DOMANS

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 A/Prof. Thomas Balle

Contact Details:
E-mail: thomas.balle@sydney.edu.au
Office: Badham Building Room 501

Background:
1997 M.Sc. Chem. Eng.
2002 Ph.D. Medicinal Chemistry
2002-2003 Medicinal Chemist, Pharmaceutical Industry
2003-2012 University of Copenhagen, Denmark
2012- Faculty of Pharmacy, USYD

Theme Leader for the Mental Health Research Theme: http://sydney.edu.au/pharmacy/our-research/themes/mental-health/

Research Interests:
Ligand gated ion channels as drug targets
Drug discovery
Nicotinic Acetylcholine Receptors, GABA Receptors
Structure based drug design & Molecular Modelling
The University of Sydney Page 4
Olsen et al, Journal of Biological Chemistry, JBC, 2014, 289, 24911-24921
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MACROMOLECULES AS DRUG TARGETS

THE BEGINNING OF MODERN PHARMACOLOGY

Langley J; J Physiol 1901, 27(3): 224–236

J. Physiol., 36, 347-384 (1907)

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MACROMOLECULES AS DRUG TARGETS

THE BEGINNING OF MODERN PHARMACOLOGY

In 1901, Langley challenged the

hypothesis that drugs act at nerve endings Langley introduces
by demonstrating that nicotine acted at receptors!
sympathetic ganglia even after the
degeneration of the severed preganglionic
nerve endings. In 1905/1907 he introduced
the concept of a receptive substance on
the surface of skeletal muscle that
mediated the action of a drug. It also
postulated that these receptive substances
were different in different species because
nicotine-induced muscle paralysis in
mammals but not in crayfish

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WHAT DO DRUGS INTERACT WITH?

DRUGS ARE CHEMICALS THAT INTERACT WITH OTHER CHEMICALS

– Common classes of drug targets

– Lipids
– Carbohydrates
– Nucleic acids
– Proteins

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DRUGS INTERACTING WITH LIPIDS

Example: Amphotericin B

– Antifungal drug used intravenously for systemic fungal infections

– The only effective treatment for some infections
– Originally extracted from Streptomyces nodosus, a filamentous
bacterium, name originates from the chemical's amphoteric
properties.

– Amphoteric from the Greek word amphoteroi (ἀμφότεροι)

meaning "both"

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DRUGS INTERACTING WITH LIPIDS

Amphotericin B

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From Baginski, Mol. Pharmacol. 1997, 52, 560-570
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DRUGS INTERACTING WITH CARBOHYDRATES

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From: Discovery Medicine, 2009, 8(43):247-252
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DRUGS INTERACTING WITH CARBOHYDRATES

– Carbohydrates are ubiquitous and represent the most abundant

class of molecules in nature.
– All cell surfaces are coated with complex carbohydrates where
they act as recognition molecules for other cells, functional
molecules, and pathogens.
– Carbohydrates are involved in disease indications as diverse as
inflammation, cancer, and infectious disease.

– Not many drugs interacting with carbohydrates – but multiple

examples of drugs mimicking them, e.g. glycomimetics

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DRUGS INTERACTING WITH CARBOHYDRATES

GLYCOMIMETICS

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From: Discovery Medicine, 2009, 8(43):247-252
 Protein structure

– Primary, secondary, tertiary and quaternary structure

Primary Structure - sequence

Secondary structure - Fold Quarternary structure –

arrangement of two or more chains
Tertiary structure –
3D arrangement

β-sheet
α-helix

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DRUGS INTERACTING WITH NUCLEIC ACIDS

– DNA has two types of

grooves:
– The MAJOR GROOVE has
the nitrogen and oxygen
atoms of the base pairs
pointing inward toward Major
the helical axis
– The MINOR GROOVE has
nitrogen and oxygen Minor
atoms pointing outwards;
– important because the
major groove is more
dependent on base
composition and may be
the site for protein
recognition of specific
DNA sequences or regions

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From Nature Education, 2013
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DRUGS INTERACTING WITH NUCLEIC ACIDS

Dactinomycin / Actinomycin D bound to DNA

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Hou et al, Nucleic Acids Res. 2002, 30, 4910
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DRUGS INTERACTING WITH PROTEINS

– Drugs often bind in deep pockets in the interior of the protein

– Binding on surface (shallow pockets) also possible – may prevent
protein-protein interactions

– To undderstand how drugs interact with receptors we need know

something about protein structure

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MACROMOLECULES AS DRUG TARGETS

FOUR MAIN TYPES OF RECEPTORS

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EXAMPLE GPCR

Drugs bind in burried pockets

Cyanopindolol

Warne et al, 2008 Nature 454: 486–492

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MACROMOLECULES AS DRUG TARGETS

ENZYMES - ACETYLCHOLINE ESTERASE

Electrostatic and shape complementarity

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Picture from http://opm.phar.umich.edu/
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DRUG-RECEPTOR INTERACTIONS

WHAT DETERMINES BINDING OF DRUGS TO MACROMOLECULES?

Drug-receptor interactions
Non-covalenet interactions important for drug binding to receptors
Examples

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DRUG-RECEPTOR INTERACTIONS

At equilibrium, the amount of drug bound

to receptor is determined by the difference
in free energy between the drug-receptor
complex and the two seperate entities in
solution

Drug receptor interactions = physical chemistry

Physical chemistry = something you have learned before

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DRUG-RECEPTOR INTERACTIONS

LAW OF MASS ACTION

A Drug (D) and a Receptor (R) combines to a Drug-Receptor

complex (DR) at a rate which is dependent on concentration of the
drug and the concentration of the receptor

k1
[D] + [R] [DR]
k2 D = Drug
R = Receptor
k2 [D][R] DR = Drug-Receptor Complex
= KD =
k1 rate for association
k1 [DR]
k2 = rate for dissociation
KD = Dissociation constant
1 KA = Association constant
= KA
KD
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 DRUG-RECEPTOR INTERACTIONS
DRUG-RECEPTOR INTERACTIONS

Bioactive Conformation

H2O H2O

H2O H2O H2O H2O H2O

H2O H2O
H2O
H2O H2O
global energy H2O
minimum H2O
H2O H2O H2O
H2O H2O
H2O ∆G = - RTlnK
∆Gconf H2O
H2O
H2O H2O
H2O
H2O H 2O
H2O H2O
H2O
H2O H2O H2O
H2O H2O
H2O H2O H2O
bioactive H2O
conformation
When comparing the efficiency of two drugs
we usually ignore the conformational
change of the receptor because two drugs
Interactions between drug and receptor with similar binding mode expected to
influence the recepto conformation to the
Desolvation same degree – i.e. term cancells out when
Conformational change of drug comparing the two situations
Conformational change receptor - Relative binding energies much easier to
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determine than absolute Page 23
 DRUG-RECEPTOR INTERACTIONS
DRUG-RECEPTOR INTERACTIONS

To have high affinity, A drug must

bind In a low energy conformation

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DRUG-RECEPTOR INTERACTIONS

BINDING FREE ENERGY

DG = DGInter + DGConf - DGSolv

The interaction energy can be split into individual contributions

from................

DGInter = DGH-Bonds + DGElectrostatic + DGvdW

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DRUG-RECEPTOR INTERACTIONS
VAN DER WAALS INTERACTIONS

EvdW = where A and B are repulsive and attractive term coefficients

Energy

r
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DRUG-RECEPTOR INTERACTIONS
DRUG-RECEPTOR INTERACTIONS
ELECTROSTATIC INTERACTIONS

Eelec = , where ε is the dieletric constant

of the solvent (or vacuum)

Energy

same charges – repulsive

( positive energy – not good)

r
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 DRUG-RECEPTOR INTERACTIONS
ELECTROSTATIC INTERACTIONS

Eelec = , where ε is the dieletric constant

of the solvent (or vacuum)

Energy
r

opposite charges – attractive

( negative energy –good)

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DRUG-RECEPTOR INTERACTIONS
HYDROGEN BOND

In principle an electrostatic interaction

Angular dependence makes it a little more complicated.

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MOLECULAR INTERACTIONS

Summary of data obtained from the protein databank (PDB)

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Bissantz et al, J. Med. Chem. 2010, 53, 5061–5084
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MOLECULAR INTERACTIONS

WATER MOLECULES ARE INTEGRAL PARTS OF PROTEINS

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Bissantz et al, J. Med. Chem. 2010, 53, 5061–5084
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MOLECULAR INTERACTIONS
HYDROGEN BONDS

Hydrogen bonds
are directional

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Bissantz et al, J. Med. Chem. 2010, 53, 5061–5084
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MOLECULAR INTERACTIONS
HYDROGEN BONDS
H-bond distances
are measured
from heavy atom
to heavy atom

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Bissantz et al, J. Med. Chem. 2010, 53, 5061–5084
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MOLECULAR INTERACTIONS
RELATIVE STRENGHT HYDROGEN BOND ACCEPTORS

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Bissantz et al, J. Med. Chem. 2010, 53, 5061–5084
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MOLECULAR INTERACTIONS
CATION-PI INTERACTIONS

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Bissantz et al, J. Med. Chem. 2010, 53, 5061–5084
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MOLECULAR INTERACTIONS
HALOGEN BOND

Halogen bonding
More blue = more positive

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Bissantz et al, J. Med. Chem. 2010, 53, 5061–5084 Beale et al, Chem. Soc. Rev., 2013, 42, 1667--1680
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MOLECULAR INTERACTIONS
NON-COVALENT INTERACTIONS - SUMMARY

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Bissantz et al, J. Med. Chem. 2010, 53, 5061–5084
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 DD2 + DD3 WORKSHOPS

– Research Led Teaching

– Professional Drug Discovery Software: Schrodinger MAESTRO

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 DD2 + DD3 WORKSHOPS

– Identify lead molecule and optimise it

WORKFLOW
– Download protein structure and ligand database
– Prepare both
– Dock ligands to protein and select lead compound
– Optimise lead compound using visual clues from binding site
energetic map
– Repetitive process – design dock – evaluate … and repeat

– Report – prepare a figure of your final optimised compound

highlighting important drug receptor interactions
– Figure should be accompanied by an INFORMATIVE figure caption –
max 200 words – (strict limit)

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 DD2 + DD3 WORKSHOPS

– Introduction Videos:
– https://www.schrodinger.com/training/videos/all-maestro-videos/starting-maestro
– https://www.schrodinger.com/training/videos/all-maestro-videos/useful-keyboard-shortcuts
– https://www.schrodinger.com/training/videos/all-maestro-videos/selecting-and-including-
entries-project-table
– https://www.schrodinger.com/training/videos/all-maestro-videos/importing-structure-file
– https://www.schrodinger.com/training/videos/all-maestro-videos/working-maestro-projects
– https://www.schrodinger.com/training/videos/docking-receptor-grid-generation
– https://www.schrodinger.com/training/videos/docking-ligand-docking
– https://www.schrodinger.com/training/videos/docking-virtual-screening
– https://www.schrodinger.com/training/videos/ligand-preparation
– https://www.schrodinger.com/training/videos/protein-preparation

– MUST watch before entering tutorial room

– Each video is 1-4 mins long

– Much more material available here – free lectures, videos and
tutorials
– https://www.schrodinger.com/videos

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 PROTEIN DATA BANK available on google play and
Apple store

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