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Ion Channel Drug Discovery
Computational Drug Discovery
Presented byA/Prof Thomas BalleSydney School of PharmacyBrain and Mind Centre
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Ion Channel Drug Discovery
• Primary focus: Pentameric ligand gated ion channels• GABAA, Nicotine, Serotonin 5-HT3 and Glycine receptors
• Multiple different subunits, complex assembly pattern, complex pharmacology
• Receptors assembled in different stoichiometric forms -“subtypes of subtypes”
• “Novel” interfaces represent novel opportunities for drug discovery
• Identification, characterization and de-orphanisation of novel drug binding sites
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3
α4
β2 β2
α4
α4
(α4)3(β2)2
-9 -8 -7 -6 -5 -4 -3 -20
25
50
75
100 EC50: 3.2 µM
log[ACh]
% o
f max
imal
AC
h
α43Mβ24:1
GABA
GABA + Diazepam
Lindquist & Birnir, J. Neurochem. 2006
-1 0 -9 -8 -7 -6 -5 -4 -3 -2
0 .0
0 .2
0 .4
0 .6
0 .8
1 .0
lo g [A C h ] \M
I/I1
mM
AC
h
A C h
A C h + N S 9 2 8 3 (3 1 .6 µ M )
E C 5 0 : 1 .1 µ M
E C 5 0 : 9 3 µ ME C 5 0 : 0 .1 1 µ M
Allosteric Modulators – Benzodiazepine type modulation
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Techniques
– Dry Lab
– Computer aided drug design– SAR analysis– Homology modeling– Pharmacophore modeling– Docking, fragment docking– Scaffold hopping– Molecular dynamics– Free energy perturbation
– Wet Lab
– Oocyte electrophysiology– Molecular biology– Assay development– Screening– Compound characterisation– Radioligand binding assays
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Techniques – Docking – Molecular Dynamics
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Oocyte electrophysiology
6
α mRNA β mRNA
Current (nA)
Time (s)
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What we would like from DDI
– DDI PhD scholarships– DDI seed funding
– Medium - High-through put screening capabilities
– Access/collaborations large scale protein expression + X-Ray crystallography/Cryo-EM
– Access/collaborations Medicinal chemistry
– Access/collaborations using slice electrophysiology– Access/collaborations in other behavioral models
– Access to ADME
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Ion Channel Drug Discovery Team
Philip Ahring Mary Collins
Thomas Balle