Experimental data guided docking allows to elucidate the molecular basis of drug-

transporter interaction

Gerhard F. Ecker

Pharmacoinformatics Research Group Department of Medicinal Chemistry, University of Vienna

Althanstrasse 14, A-1090 Wien, Austria gerhard.f.ecker@univie.ac.at; http://pharminfo.univie.ac.at

Transporters involved in ADMET

Nature Reviews Drug Discovery 9, 215-236 (March 2010)

Drug Transporter

Aller et al. Science 2009

Major Challenge: Polyspecificity

QSAR Studies of Propafenones

N

OH

NH N

H( )n

n = 0-2

NR

O H

O

O

calcd logP

log(

1/IC

50)

1 2 3 4 5 6 7

-1,5

-1,0

-0,5

0,0

0,5

1,0

1,5

Ligand-based Design

NO

O

OH

Optimal distance: 3.5 -CH2-

high partial logP

steric interactions

H-bond acceptor

H-bond acceptor

π−π-interaction

π−π-interaction

1 2 3 4 5 6 7

-1,5

-1,0

-0,5

0,0

0,5

1,0

1,5

calcd logP

log(

1/IC

50)

400 compounds in house library

2D-QSAR

3D-QSAR Pharmacophormodeling

Ecker et al., J Med Chem 39:4767 Ecker et al., Mol Pharmacol 56:791 Chiba et al., J Med Chem 41:4001 Kaiser et al., J. Med Chem 50:1698 Cramer et al., ChemMedChem, 2007

Target-based Design

Aller et al., Science 2009, 323, (5922), 1718-22

SAR-driven docking/Scoring

Mouse P-gp Sav1866 Homology Models of P-gp

Docking into Protein Homology Models

Common Scaffold Clustering

N

N

N

O H

N

C H3

O

NO

O

O N

O H

Klepsch et al., PloS Comp Biol 2011

Identification of new Ligands

Docking-based classification of P-gp inhibitors

1935 compounds Dock, score take top scored run distribution Accuracy 0,75

Klepsch, JCIM 2013

So we know the molecular basis of propafenone/P-gp interaction

• Poses consistent with QSAR • Poses predictive for identifying new ligands • Docking allows classification inhibitor/non-

inhibitor

BUT

Mutating Tyr307/310 to Phe

Multiple sites for the same ligand?

Keskin BMC Structural Biology 2007 7:31

Gln132/773Arg

Parveen et al, Mol Pharmacol 2011

O NR'OH

R

O

Target-based Design - Reality

Docking into SERT

Imipramine and serotonin bind mutually exclusive Affinity loss with Y95F (1,2 kcal/mol) Carbamazepine and serotin bind simultaneously

Sarker et al, Mol Pharmacol 2010

Inclusion of Water

A novel platform for integrated data-driven drug discovery

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The Need

Explorer: www.openphacts.org

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The active Open PHACTS app ecosystem

Open PHACTS has engaged the scientific community, and many apps now consume the data within the Open PHACTS API

Thank you! Barbara Zdrazil Ishrat Jabeen Marta Pinto Rita Schwaha Lars Richter Daniela Digles Yogesh Aher Freya Klepsch Rene Weissensteiner Andreas Jurik Vasanathan Poongavanam Daria Tsareva Amir Seddik

Eric Haaksma Peter Ettmayer Oliver Krämer Peter Chiba Wilfried Gansterer Johnny Gasteiger