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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