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© Heptares Therapeutics 2018
The HEPTARES name, the logo and STAR are trade marks of Heptares Therapeutics Ltd
Heptares Therapeutics is a wholly owned subsidiary of Sosei Group Corporation
Structure-based Drug Design for GPCRs
Jana Broecker
2018-04-11, Banff (Canada)
Non-Confidential© 2018 Heptares Therapeutics
osteopo-
rosis
inflam-
mation
\
\\\\\\\\\\\\\
cancerheart
diseases
diabetesmultiple
sclerosis
asthma
schizo-
phrenia
…Alzheimer’s
cystic
fibrosis
GPCRs are involved in human diseases
1
class A
class Bclass C
class F
Non-Confidential© 2018 Heptares Therapeutics
GGDPGGTP
orthostericligand
kinase ARRARRP P P P
adenyl cyclasesphospholipasesphosphodiesterases
GGTP
ion channels…
N
C
out
in
2
• 7 transmembrane helices
• extracellular ligands
• intracellular G proteins
• transducer of signaling pathways
mem
bran
e
Human GPCRs
Non-Confidential© 2018 Heptares Therapeutics
3
Heptares’ Technology Platform
notoriously challenging
enhanced stability
validated pharmacology
Non-Confidential© 2018 Heptares Therapeutics
GPCR Thermodynamics
Understanding entropy and enthalpy
4
GPCR Structure Determination
Landmark structure reveals new drug binding site in Family B GPCRs
Computational modelling of protein, ligand, and water interactions
Computational Modelling
Controlling Receptor Kinetics
Drug kinetics by StaR® using SPRrelated to X-ray crystal structures
Heptares’ Technology Platform
Non-Confidential© 2018 Heptares Therapeutics
5
Internal 1 - Conf
Internal 2 - Conf
Internal 3 - ConfInternal 4 - Conf
Internal 5 - Conf
Internal 6 - Conf
highest-resolution GPCR structure at 1.7Å 1st back-soaked GPCR structure
>150 structures solved to date 1/3 of all structures in PDB are StaR structures
StaR® Technology Success Across GPCRome
C5a
Non-Confidential© 2018 Heptares Therapeutics
6
multiple negative allosteric modulators (NAMs) reported in the literature for thetreatment of anxiety, depression, migraine, or movement disorders
• entrance to binding pocket closed by ECL2• this may explain narrow SAR
1Dore et al., Nature, 2014, 511, 557.
Example I:1 Glutamate Receptor mGluR5
• crystallised in LCP: 2.6 Å• density of NAM mavoglurant
in the TM domain
8Å
Non-Confidential© 2018 Heptares Therapeutics
7
Example II:1 Glucagon Receptor GCGR
1Jazayeri et al., Nature, 2016, 533, 274.
multiple small-molecule antagonists have been investigated for the treatment oftype 2 diabetes
• crystallised in LCP: 2.5 Å• density of small-molecule NAM
MK-0893 outside the TM domain
• novel intracellular allosteric binding site• ligand locks TM6 in inactive
conformation
Non-Confidential© 2018 Heptares Therapeutics
81Robertson et al., Nature, 2018, 553, 111.
Example III:1 Complement C5a Receptor 1antagonists and inverse agonists of the complement system have long been ofinterest for the treatment of arthritis, Crohn’s disease, or Alzheimer’s disease
• crystallised in LCP: 2.7 Å• structure reveals non-crystallographic
ligand-mediated dimer
• density of small-molecule inverse agonist NDT9513727 between two receptors in hydrophobic pocket generated by TMs 3/4/5
• binding based on shape complementarity and a crucial contact with Trp213
Non-Confidential© 2018 Heptares Therapeutics
9
• allosteric sites are often intrinsically more druggable than orthosteric ones unique opportunities for SBDD
• SBDD remains challenging: low affinity slow kinetics high lipophilicity
(C5a)
Allosteric Sites Across GPCR Classes1
• variety of allosteric binding sites diversity of binding modes and mechanisms for allosteric control of GPCR function
ligand binding
pharmacological effect?
better drugs• maximal efficacy• reduced side effects
1Congreve et al., Trends Pharmacol. Sci., 2017, 38, 837.
Non-Confidential© 2018 Heptares Therapeutics
10
Acknowledgements
Thank you very much for your attention!
GCGR• Ali Jazayeri• Andrew S. Doré• Daniel Lamb• Harini Krishnamurthy• Stacey M. Southall• Asma H. Baig• Andrea Bortolato• Markus Koglin• Nathan J. Robertson• James C. Errey• Stephen P. Andrews• Iryna Teobald• Alastair J.H. Brown• Robert M. Cooke• Malcolm Weir• Fiona H. Marshall
C5aR1• Nathan Robertson• Mathieu Rappas• Andrew S. Doré• Jason Brown• Giovanni Bottegoni• Markus Koglin• Julie Cansfield• Ali Jazayeri• Robert M. Cooke• Fiona H. Marshall
mGlu5R• Andrew S. Doré• Krysztof Okrasa• Jayesh C. Patel• Maria Serrano-Vega• Kirstie Bennett• Robert M. Cooke• James C. Errey• Ali Jazayeri• Samir Khan• Ben Tehan• Malcom Weir• Giselle Wiggin• Fiona H. Marshall
DIBMA• Elena Segala• Gregory Verdon• James Errey
Management• Rob Cooke (VP Biomol. Structure)• Malcolm Weir (CEO)• Ali Jazayeri (CTO)• Miles Congreve (SVP Drug Disc.)
coming soon: Cambridge, UK