astronomy talk: dr alice e williamson 041115

Open Source Malaria A New Approach To Drug Discovery

Alice E Williamson

The University of Sydney@O_S_M

.Astronomy 7 4th November 2015 Justice & Police Museum

Image: Merinda Jayne Ramage

Open Source Malaria – A New Way of Finding Medicines

https://twitter.com/O_S_M

Malaria

Mosquito-borne infectious disease caused by protists of the genus PlasmodiumInfection initiated by a bite from an infected female mosquito Protists are introduced via siliva into the circulatory systemIn the liver, they mature and reproduce to cause symptoms including fever and headache

Lack of effective control and emergence of drug resistance strains

2013 Worldwide 198 million casesOver 500 000 deaths mainly in African children <5 years old10% of all deaths in Africa30–50% of hospital admissions

WHO World Malaria Report 2014 (http://www.who.int/malaria/publications/world_malaria_report_2014/en/).

http://www.who.int/malaria/publications/world_malaria_report_2014/en/

Current Treatments

Phyo, A. P.; et al. Lancet 2012 379, 1960Photograph Jin Liwang/AP from: http://www.theguardian.com/science/2015/oct/05/youyou-tu-how-maos-challenge-to-malaria-pioneer-led-to-nobel-prize

O

O

Me

HMe

O

H

HOO

Me

artemisinin

http://www.theguardian.com/science/2015/oct/05/youyou-tu-how-maos-challenge-to-malaria-pioneer-led-to-nobel-prize

Current Treatments

Phyo, A. P.; et al. Lancet 2012 379, 1960Article: http://www.theguardian.com/society/2015/feb/20/drug-resistant-malaria-threatens-to-spread-from-burma-say-researchers

O

O

Me

HMe

O

H

HOO

Me

artemisinin

http://www.theguardian.com/society/2015/feb/20/drug-resistant-malaria-threatens-to-spread-from-burma-say-researchers

Traditional Drug Discovery

D. W. Light and J. R. Lexchin, British Medical Journal 2012, 345, e4348. (DOI: 10.1136/bmj.e4348)

Market Incentive

Address by WHO Director General Margaret Chan, Regional Committee for Africa, 64th Session, Cotonou, Republic of Benin, 3rd Nov 20141

[1] http://www.who.int/dg/speeches/2014/regional-committee-africa/en/[2] Report of the Consultative Expert Working Group on Research and Development: Financing and Coordination, World Health Organization, 2012, ISBN: 978 92 4 150345 7, http://www.who.int/phi/cewg_report/en/

http://www.who.int/dg/speeches/2014/regional-committee-africa/en/

Market Incentive

Address by WHO Director General Margaret Chan, Regional Committee for Africa, 64th Session, Cotonou, Republic of Benin, 3rd Nov 20141

[1] http://www.who.int/dg/speeches/2014/regional-committee-africa/en/[2] Report of the Consultative Expert Working Group on Research and Development: Financing and Coordination, World Health Organization, 2012, ISBN: 978 92 4 150345 7, http://www.who.int/phi/cewg_report/en/

Research and Development to Meet Health Needs in Developing Countries: Strengthening Global Financing and Coordination2

http://www.who.int/dg/speeches/2014/regional-committee-africa/en/

An Open Source Approach

http://

Open Source Malaria

The Six Laws of Open Source Research First Law: All data are open and all ideas are shared

Second Law: Anyone can take part at any level Third Law: There will be no patents

Fourth Law: Suggestions are the best form of criticism Fifth Law: Public Discussion is much more valuable than private email

Sixth Law: The project is bigger than, and is not owned by, any given laboratory

Landing page:www.opensourcemalaria.org

M. Robertson, P. Ylioja, M. Woelfle, M. Robins, A. E. Williamson, K. Badiola, P. Willis, P. Olliaro, T. N. C. Wells and M. H. Todd, Parasitology 2014, 141, 148–157. (DOI: 10.1017/S0031182013001121)

http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=9137285&fileId=S0031182013001121

Adhering to the Six Laws





Robertson, N. M.; et al. Parasitology 2014, 141, 148. (DOI: 10.1017/S0031182013001121)Badiola, K. A.; et al. Chem. Sci. 2014, 6, 164. (DOI: 10.1039/C4SC02128B)


http://pubs.rsc.org/en/Content/ArticleLanding/2015/SC/c4sc02128b#!divAbstract






Robertson, N. M.; et al. Parasitology 2014, 141, 148. (DOI: 10.1017/S0031182013001121)Badiola, K. A.; et al. Chem. Sci. 2014, 6, 164. (DOI: 10.1039/C4SC02128B)


http://pubs.rsc.org/en/Content/ArticleLanding/2015/SC/c4sc02128b#!divAbstract

Project Background

Gamo F-J.; et al. Nature. 2010, 465, 305. (DOI:10.1038/nature09107)

Series 1

N

Me

Me

F

OSM-S-5 404 nMTCMDC 123812 330 nM

O

ONH2

O

N

Me

Me

F

OSM-S-6 54 nMTCMDC 123794 345 nM

O

ON

O

H

NN

O

PhMe

Me

Gamo F-J.; et al. Nature. 2010, 465, 305. (DOI:10.1038/nature09107)

Does Open Work?

Series 1B: ‘Near-Neighbours’

Crowdsourced, Open Undergraduate Lab Classes

Series 2 and 3

NMe

SOO

NN

N NMe2

O

Cl

Triazolourea singleton

TCMDC 134395 767 nM

N

N

SNH2 S NH2

OO

Aminothienopyrimidine Series

TCMDC 135294 150 nMOSM-S-106 36 nM

Series 4: Triazalopyrazines

NN

NN

ArOR2R1N

NN

NN

O Ar

ORAr'

The Triazolopyrazines - Series 4 of the OSM Project

Amides Ethers

NN

NN

ArORN

NN

NN

O

O

The Triazolopyrazines - Series 4 of the OSM Project

Amides MMV670652

Ar'

F

FCN

F

F

•  Pfizer ! hit-to-lead work funded by MMV performed by a CRO

•  Series includes many potent compounds

•  Evidence from parasite ion regulation assays that these compounds may be PfATP4 inhibitors

Aims:

1.  Lead optimisation, to improve solubility and metabolic stability while maintaining potency

2.  Validation of PfATP4 activity as mechanism of action

PfATP4

EA Winzeler, K Kirk et al. Cell Host Microbe. 2013, 227-237 (10.1016/j.chom.2012.12.006)

Amides

NN

NN

O

FF

ClH

MMV639565 ED90 = 6.3 mg/Kg

NN

NN

O

FF

CNOMe

MMV669844 99.9% inhibition of parasitemia

snapshot Peters test (4 x 50 m/Kg)

High School Students

with Sydney Grammar School

NN

NN

Cl N

NN

NN

ClN

NN

NN

Cl

N

NN

NN

Cl

CN

Undergraduates

NN

NN

O

Ar X

NN

NN

O

Ar X FF

NN

NN

O

Ar XO

O

NN

NN

O

Ph

NN

NN

O

Ph

NN

NN

O

Ph

NN

NN

O

Ph

Cl

Cl

Cl

Special Students Programme

with Sebastien Darth with Christina XiaBenjamin Xie and Thomas Yorke

Talented Students Programme

Sharing Chemistry Data

Vs.


InChI=1S/C12H7ClF2N4O/c13-9-5-16-6-10-17-18-11(19(9)10)7-1-3-8(4-2-7)20-12(14)15/h1-6,12Hand

InChI=1S/C6H7NO/c8-5-6-3-1-2-4-7-6/h1-4,8H,5H2to

InChI=1S/C18H13F2N5O2/c19-18(20)27-14-6-4-12(5-7-14)17-24-23-15-9-21-10-16(25(15)17)26-11-13-3-1-2-8-22-13/h1-10,18H,11H2

ClC1=CN=CC2=NN=C(C3=CC=C(OC(F)F)C=C3)N21and

OCC1=CC=CC=N1to

FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C(OCC4=CC=CC=N4)=CN=C3


F

N

Me

Me

OO O

OHMe

OSM-S-100


N NN

N

O

O

FF

HN

Cl

MMV6689580.25

sol (pH 6.8) 54 µMHLM CLint 50 µL/min/mg

HLM T1/2 20 min

Potencies (red): Pfal in µM

HN

F

MMV6695430.276

HLM CLint 11 µL/min/mg

HLM T1/2 86 minRLM CLint <14 µL/min/mg

RLM T1/2 >120 min

F

HN

MMV6695420.18

sol (pH 7.4) <2.5 µMHLM CLint 72 µL/min/mg

HLM T1/2 13.6 minRLM CLint 290 µL/min/mg

RLM T1/2 6 min

Cl

MMV670246>5

sol (pH 7.4) <2.5 µMHLM CLint 8.6 µL/min/mg

HLM T1/2 115 minRLM CLint 15 µL/min/mg

RLM T1/2 113 min

HN

Cl

MMV6698500.652

sol (pH 6.8) 16.8 µMHLM CLint 18 µL/min/mg


RLM T1/2 56 min

HN

FF

MMV6707670.191

HLM CLint 22 µL/min/mg


RLM T1/2 27 min

HN

FCl

MMV6709440.14

sol (pH 6.8) >200 µMHLM CLint 20 µL/min/mg


RLM T1/2 105 min

HN

NF3C

N

MMV669000>10

MMV6690011.33

HN

Cl

MMV6690020.379

HN

Cl

MMV669003>10

HN

O

MMV669010>10

NN

N

MMV669011>10

HN

N

O

N

MMV669022>10

N

MMV6691043.56

MMV669023>10

NN

SO O

MMV669020>10

NO

MMV6690241.35

HN

MMV6690211.59

HN

MMV669026>10

HN

N

MMV6690273.17

HN N

Cl

MMV6691051.06

HN

F

MMV6698493.74

N

MMV670768>10

F

HN

F

MMV6716545.576

Cl

MMV6716760.332

HN

Cl

Cl

MMV6716770.309

HN

ClCF3


https://www.ebi.ac.uk/chembl/malaria/

OSM and Beyond

Open Source Malaria opensourcemalaria.org@O_S_MASAP award video (https://www.youtube.com/watch?v=gCOokjOiVTc)

Open Source TB @OpenSourceTB

Open Source Pharma http://www.opensourcepharma.net/@OSPInfo

http://opensourcemalaria.org

https://www.youtube.com/watch?v=gCOokjOiVTc

New challenges

N N

NN

Cl N

N N

NN

Cl N

N N

NN

Cl

N

N N

NN

Cl

1 2 3 4

CN

Targets

Cl

N

N

NH2

NH2Et

New challenges

N N

NN

Cl N

N N

NN

Cl N

N N

NN

Cl

N

N N

NN

Cl

1 2 3 4

CN

Targets

New Challenges

N N

NN

Cl N

N N

NN

Cl N

N N

NN

Cl

N

N N

NN

Cl

1 2 3 4

CN

Targets

ClN

Et OEt

O

ClN

OEt

ClN

OMeEt

Cl

N

N

NH2

NH2Et

NaOMe

MeO

OMe

OMe

H2N

NH

NH2

$144 for 500 g

$750 per dose!

New Challenges

N N

NN

Cl N

N N

NN

Cl N

N N

NN

Cl

N

N N

NN

Cl

1 2 3 4

CN

Targets

ClN

Et OEt

O

ClN

OEt

ClN

OMeEt

Cl

N

N

NH2

NH2Et

NaOMe

MeO

OMe

OMe

H2N

NH

NH2

$144 for 500 g

$750 per dose!

500 g in theory produces 820 g lets assume 10% yield, so 82 g

82/0.05 = 1640 doses = $1.23 million

The Analogy

http://bit.ly/110pMAP

The Analogy

http://bit.ly/13zFJ6s

Acknowledgements

The University of Sydney: Joanna Ubels, Thomas Macdonald, Tianyi Zheng, Paul King, Sebastien Darth, Benjamin Xie, Christina Xia and Tom York Edinburgh University: Patrick Thompson, Jamie Scott GSK: Javier Gamo, Felix Calderon, Lluis Ballell, Julia Castro-Pichel

ANU: Kiaran Kirk, Adele Lehane, Melanie Rigeway, Adelaide Dennis Monash: Sue Charman, Karen White Pfizer: Scott Obach, Christine Orozco Columbia University: David Fidock Sydney Grammar School: Erin Sheridan, Trent Wallis and Class Cambridge MedChem

Consulting: Chris Swain

WHO/TDR: Piero Olliaro MMV: Tim Wells, Paul Willis, Jeremy Burrows Southampton: Jeremy Frey and team ChEMBL: John Overington, Iain Wallace, George Papadatos Eskitis: Vicky Avery, Sandra Duffy, Sabine Fletcher Melbourne: Stuart Ralph, James Pham AstraZeneca: Asclepia: Frederick DeRoose Others Chris Southan,

Murray Robertson

Matthew Todd Paul Willis Kiaran Kirk

astronomy talk: dr alice e williamson 041115

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