Application of Sosei Heptares GPCR StaR® platform for ...€¦ · Based Drug Design & Hit...
Transcript of Application of Sosei Heptares GPCR StaR® platform for ...€¦ · Based Drug Design & Hit...
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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 – [email protected]
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Unpublished in-house structures Ox1/Ox2, bound to different ligands and with different water networks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