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In Silico Drug Discovery Outside the Traditional Big Pharma Model Dr Martin J. Slater

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Page 1: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

In Silico Drug Discovery Outside the Traditional Big Pharma Model

Dr Martin J. Slater

Page 2: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

© Cresset

Cresset summary

> Founded in 2002 by Dr. Andy Vinter – initial Welcome Trust funding> Located in Cambridge, UK> Primary market pharmaceutical and biotech R&D> 14 of the top 20 pharmaceutical companies use Cresset technology in their

research programmes> 200 collaborative projects delivered to global clients> Other markets include flavour and fragrance, agrochemical and chemicals

NN

Br

F FF

SH2NOO

Page 3: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

© Cresset

Detailed electrostatics decode SAR

4

Has an effect here – more negative

Also has an effect here – more positive, dipole across ring from electronegative Fluorine

Difference plot: regions where each molecule has stronger electrostatics

And here – Ar face more negative, F is electron withdrawing

Page 4: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

© Cresset

Small molecule drug discovery: The beginning

Using whatever you know to progress from target to a chemical starting point

Use disease biology to furnish models & assays• biochemical • biophysical • phenotypic

Pharmacological dataBioinformaticsChemogenomicsProteomics

HTS ‘random’ screeningfocused / selected librariesfragment screening

Hitdiscovery

Information based approachesPractical approaches

Targetvalidation

Library design, virtual screening, fragment screening, rational design, cheminformatics

Page 5: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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Small molecule drug discovery: The end of the beginning

Using whatever you’ve ‘learned’ to progress from the chemical starting point

Build chemical SARof series, iteratively address potency, selectivity, ADMET property issues

3D super-alignment,bioactive conformer elaboration,binding mode prediction,rational design, 3D-QSAR,multi-parameter optimization

Leadoptimizationand candidate selection

Bioisosteric replacement

Scaffold hopping

Exemplify, analogues

……start again

Patent protection, findback-up series

Information based approachesPractical approaches

Page 6: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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Comparative costs

7

Chemist FTE’sBiologist FTE’s

ConsumablesEquipmentLabspace

$300k-3000k per project

Modeling FTE’s

SoftwareCPU’s

$10k-50k per project

Considerable cost savings to be made from increasing efficiency of, or just reducing, lab based FTE requirements

>>

Page 7: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

© Cresset

Best in breed software for ligand centric molecular modeling workflows

Commitment to continued development to push the boundaries

Cutting edge software

8

Page 8: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

© Cresset

Bioisosteres Bioisosteric groups

Biologically relevant molecular comparisons

Page 9: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

© Cresset

> Jump into new areas of chemical space, e.g. to replace peptides with non-peptides

> Increase your screening hit rates> Improve the properties of your hits> Increase the diversity of your lead compounds

> Decipher complex SAR and communicate the results> Build detailed pharmacophores> Virtually screen thousands of compounds on your desktop> Design new molecules with the ideal activity and property

profile

> Move to new series and non-obvious IP by swapping scaffolds

> Find the best R-groups from your reagents> Grow fragments and molecules to make new interactions

with your protein> Generate highly innovative ideas for your project

> Assess biological impact of chemical variations> Understand causes of activity across series and perfect

the design of new compounds> Effectively communicate your ideas and results> Rapidly navigate complex SAR, highlighting key activity

changes

Cresset software

Page 10: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

© Cresset

Ligand-based molecular modeling workflows and data handling

11

Page 11: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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3D activity cliffs: Pairwise analysis - Disparity matrix

Click to cell to send to 3D window

Molecules

Molecules

Coloured by disparitystrong colours SARSortable table

Page 12: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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Field differences inform decisions

13

Difference plot: Regions where each molecule has stronger electrostatics

Page 13: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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3D Quantitative and qualitative: 3D-QSAR and Activity Atlas

14

Agree on importance of phenyl group

Activity Atlas gives more detail about ideal halogenation pattern (large activity cliffs!)

QSAR gets more detail about undesired sterics

QSAR gets more information about substitution here (no big activity cliffs here)

Activity Atlas gives more definition of phenyl electrostatics

Page 14: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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Adenosine Receptors: A1, A2a, A3

More +veMore -ve

Steric BadSteric Good

Page 15: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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3D Rism using XED ff3: 1TT1 – Amber vs XED

16

-2.59Kcal Stable (just) -13.33Kcal Stable (very)

Amber XED

Extensive H-bonds suggest stability

Page 16: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

© Cresset

XED driven protein fields: 1LPZ – With stable water

17

Page 17: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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G-protein binding energy ‘v’ pharmacology

> The G protein binding energy correlates well with observed pharmacology> The two conformers of CGP-12177 correspond to the latest estimate of its activity as a partial

agonist> The two S-OH enantiomers of Fenoterol indicate antagonist action and the neutral

antagonists have split effects although Alprenolol has both in the 'antagonist region

18

Inverse Agonist

Neutral Antagonist

Full Agonist

Partial Agonist

Not clear

Page 18: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

© Cresset

A team of experienced scientists with access to cutting edge software

Contract research

19

Page 19: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

© Cresset

As your science partner we share your goals and challenges

Page 20: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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A Cresset services year: projects

Page 21: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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New inhibitors for a novel osteoarthritis target via a three-way collaboration with Cresset consulting services

Case Study

22

Page 22: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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Cresset consulting services case study

A three-way Services Collaboration on an MRC funded Osteoarthritis project:

Professor Drew Rowan Musculoskeletal Research Group,Institute of Cellular Medicine,University of Newcastle

Prem Meghani and Lorna Duffy Sygnature Discovery Ltd

Martin SlaterCresset

Andy BaxterConsultant

Page 23: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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Background: Osteoarthritis & rheumatoid arthritis

What is osteoarthritis?

Page 24: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

© Cresset

Validation: Protease-X inhibition reduces OA severity

Page 25: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

© Cresset

PotencySelectivity

Potency

Clash Fxa Tyr

Clash thrombin TrpPlasmin GluPotency

Selectivity

Clash Urokinase

Alternative dibasic analogueBOMCL19b_4 (6.3nM) ambiguous P2 –P1’ P2’ substituent and ambiguous P3-P4 substituent conformation not selective against FXa

Most potent P3-P4 substitution of cpd21 analogues less ambiguous conformation compared with cpd 21 amine

Selectivity / potency profile: Best dibasic template

SNH

O O

N

O

N O

NH 2+

H2N

O

HN+

NH 2

HNS

NH

OO

N

O O

H2N+

NH 2

NH 2

HN

O

Page 26: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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SNH

O O

N

O

NH 2+

H2N

HN+

NH 2

SNH

O O

N

O

N O

NH 2+

H2N

O

SNH

O O

N

O

N O

O

HN+

NH 2

ACB

Full template A-B frag A-C frag B-C frag

Search molecule/fragment strategy

Page 27: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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Virtual screening hit analysis

> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model

> Key features present in cpd 21 are missing in 154 but primarily low activity likely due to an inferior S1 binding fragment

> 119 is devoid of the sulphonamide portion but has a basic tail reminiscent of the template –suggesting possible fusion of 154 and 119 features

Page 28: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

© Cresset

P1’-P2’ pocket electrostatics and SAR

Tyrosine (hydrophobic) NCL1078 (2075 nM) NCL1075 (2237 nM) NCL 1077 (2284 nM) NCL 1071 (3663 nM)

Tyrosine (negative) NCL1069 (149 nM) NCL1057 (315 nM NCL 1073 (647 nM) NCL 1070 (2074 nM)

P1’-P2’pocket

P1’-P2’pocket

Page 29: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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> Proposed hetero system provided relatively rapid synthetic evaluation and systematic optimization

> Still one problem to solve…….but almost there

30

Newcastle experiments performed by: W Hui, DJ Wilkinson, A Destrument, S Watson

Results: Protease-X inhibition reduces OA severity - NCE

(fold over Protease-X)

Page 30: In Silico Drug Discovery Outside the Traditional Big …...> Screening hits 154, 234 and 119 were analysed for 3D alignment with the cpd 21 binding model > Key features present in

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Acknowledgements

Chemistry: SygnatureLorna DuffyPrem Meghani

Biology: University of NewcastleProf. Drew RowanW HuiDJ WilkinsonA DestrumentS Watson

Modeling: CressetAndy Vinter

OtherAndy Baxter


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