1

Mathew Leveridge, Greg Osborne, Chris de Graaf , Kirstie Bennett, Stacey Southall, Andy Doré, Matt Barnes, Alastair J. H. Brown, Mathieu Rappas, Oliver Schlenker, Christine Oswald.

GPCR’s and StaR® Technology

Sosei Heptares Hit Finding Approaches

© Sosei Group 2020. HEPTARES name, the logo [and StaR] are trade marks of the Sosei Group.

Application of Sosei Heptares GPCR StaR® platform for Structure Based Drug Design & Hit Identification

Sosei Heptares, Cambridge UK – Mat.leveridge@soseiheptares.com

GPCR binding determinants: Lipophilic hotspots, water networks

The Stabilized Receptor (StaR®) is at the core of our SBDD platform

Proprietary GPCR databases enabling GPCR Structure-Based Drug Design

StaR® enabled high Concentration Fragment Screening: mGlu5

Allosteric modulators of GPCR functionCrystal structures realised by StaR® receptors.

Water mediated receptor-ligand interactions in crystal structures

Lemborexant

Suvorexant

EMPA

dual OX1/OX2

dual OX1/OX2

OX2 selective

Targeting lipophilic hotspots and unhappy water sites determine

ligand binding

Trapped unhappy water in Ox1

OX2/OX1 selectivity:

Binding pocket Ox1 (A3x33) > Ox2 (T3x33)

Multiple in-house OX1/OX2 crystal structures for SBDD:- Variable ligand binding modes – pharmacophore models- Consideration water networks in docking, FEP- Design opportunities smaller ligands w. different properties

Examples

Pharmacophore?

Unpublished in-house structures Ox1/Ox2, bound to different ligands and with different water networks

WaterFLAP: MIF based water

networks post short MD

WaterMap: MD based hydration site thermodynamics

C sp3 probe 1 kcal/mol

C sp2 probe -2.8 kcal/mol

Water probe -5 kcal/mol

GRID Probes:

Pseudo apo water G: Energetically very unhappy water in A2A

Ligand perturbated G: Energetically stabilised water in A2A

WaterFLAP water energetics A2A QSAR

Collaboration S. Cross, G. Cruciani

Rappas, M. et al., J. Med. Chem. (2019)

• mGlu5 example of a Class C receptor.

• mGlu5 stabilisation carried out with a negative allosteric modulator (NAM) with binding site in the transmembrane region of the receptor

• Very dramatic increase in expression with the StaR® receptor over the WT mGlu5 receptor.

• StaR® has significantly higher DMSO tolerance allowing more flexibility in screening concentrations.

• Bespoke Class C fragment set and the general Heptares fragment library yielded tractable hits for mGlu5 and mGlu2 (6-8% hit rate, >30% cut off)

•This lead to a candidate molecule. HTL0014242