structure-based drug design for gpcrs - smalp.netsmalp.net/images/smalp_broecker.pdf ·...

© 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


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


3

Heptares’ Technology Platform

notoriously challenging

enhanced stability

validated pharmacology


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


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


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


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


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


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.


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

structure-based drug design for gpcrs - smalp.netsmalp.net/images/smalp_broecker.pdf ·...

Documents