Universiteit Leiden

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Division of Drug Discovery & Safety


Here you can find our most recent research publications


Publications 2016:


Structure-activity relationships of the sustained effects of adenosine A2A receptor agonists driven by slow dissociation kinetics.
Hothersall JD, Guo D, Sarda S, Sheppard RJ, Chen H, Keur W, Waring MJ, IJzerman AP, Hill SJ, Dale IL, Rawlins P.
PubMed PMID: 27803241. 

Kinetic Profile of Neuropeptide-Receptor Interactions.
Nederpelt I, Bunnik J, IJzerman AP, Heitman LH.
Trends Neurosci. 2016 Oct 25. pii: Review. PubMed PMID: 27793433.

Data-driven approaches used for compound library design, hit triage and bioactivity modeling in high-throughput screening. Paricharak S, Méndez-Lucio O, Chavan Ravindranath A, Bender A, IJzerman AP, van Westen GJ.
Brief Bioinform.
2016 Oct 27. pii: bbw105. [Epub ahead of print] PubMed PMID: 27789427.

In search of novel ligands using a structure-based approach: a case study on the adenosine A(2A) receptor.
Lenselink EB, Beuming T, van Veen C, Massink A, Sherman W, van Vlijmen HW, IJzerman AP.
J Comput Aided Mol Des. 2016
Oct;30(10):863-874. PubMed PMID: 27629350.

Interacting with GPCRs: Using Interaction Fingerprints for Virtual Screening.
Lenselink EB, Jespers W, van Vlijmen HW, IJzerman AP, van Westen GJ.
J Chem Inf Model. 2016 Oct 24;56(10):2053-2060. PubMed PMID: 27626908.

Synthesis and evaluation of N-substituted 2-amino-4,5-diarylpyrimidines as selective adenosine A(1) receptor antagonists
Alachouzos G, Lenselink EB, Mulder-Krieger T, de Vries H, IJzerman AP, Louvel
J. . Eur J Med Chem. 2016 Sep 26;125:586-602. doi: 10.1016/j.ejmech.2016.09.081. [Epub ahead of print] PubMed PMID: 27718474.

The Added Value of Assessing Ligand-Receptor Binding Kinetics in Drug Discovery.
Guo D, Heitman LH, IJzerman AP.
ACS Med Chem Lett. 2016 Aug 19;7(9):819-21. doi: 10.1021/acsmedchemlett.6b00273. PubMed PMID: 27660682; PubMed Central PMCID: PMC5018870.

Kinetic binding and activation profiles of endogenous tachykinins targeting the NK1 receptor.
Nederpelt I, Bleeker D, Tuijt B, IJzerman AP, Heitman LH.
Biochem Pharmacol. 2016 Oct 15;118:88-95. doi: 10.1016/j.bcp.2016.08.004. PubMed PMID: 27501920.

 Data-Driven Derivation of an "Informer Compound Set" for Improved Selection of Active Compounds in High-Throughput Screening.
Paricharak S, IJzerman AP, Jenkins JL, Bender A, Nigsch F.
J Chem Inf Model. 2016 Sep 26;56(9):1622-30. doi: 10.1021/acs.jcim.6b00244. PubMed PMID: 27487177.

A new hERG allosteric modulator rescues genetic and drug-induced long-QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells.
Sala L, Yu Z, Ward-van Oostwaard D, van Veldhoven JP, Moretti A, Laugwitz KL, Mummery CL, IJzerman AP, Bellin M.
EMBO Mol Med. 2016 Sep 1;8(9):1065-81. doi: 10.15252/emmm.201606260. PubMed PMID: 27470144.

Controlling the Dissociation of Ligands from the Adenosine A2A Receptor through Modulation of Salt Bridge Strength.
Segala E, Guo D, Cheng RK, Bortolato A, Deflorian F, Doré AS, Errey JC, Heitman LH, IJzerman AP, Marshall FH, Cooke RM.J Med Chem. 2016 Jul 14;59(13):6470-9. doi: 10.1021/acs.jmedchem.6b00653. PubMed PMID: 27312113.

Getting personal: Endogenous adenosine receptor signaling in lymphoblastoid cell lines.
Hillger JM, Diehl C, van Spronsen E, Boomsma DI, Slagboom PE, Heitman LH, IJzerman AP.
Biochem Pharmacol. 2016 Sep 1;115:114-22. doi:10.1016/j.bcp.2016.06.006. PubMed PMID: 27297283.

5'-Substituted Amiloride Derivatives as Allosteric Modulators Binding in the Sodium Ion Pocket of the Adenosine A2A Receptor.
Massink A, Louvel J, Adlere I, van Veen C, Huisman BJ, Dijksteel GS, Guo D, Lenselink EB, Buckley BJ, Matthews H, Ranson M, Kelso M, IJzerman AP.
J Med Chem. 2016 May 26;59(10):4769-77. doi: 10.1021/acs.jmedchem.6b00142. PubMed PMID: 27124340.

Kinetic Aspects of the Interaction between Ligand and G Protein-Coupled Receptor: The Case of the Adenosine Receptors.
Guo D, Heitman LH, IJzerman AP.
Chem Rev. 2016 Apr 18. [Epub ahead of print] PubMed PMID: 27088232.

Allosteric Modulation of Kv11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias.
Yu Z, Liu J, van Veldhoven JP, IJzerman AP, Schalij MJ, Pijnappels DA, Heitman LH, de Vries AA.
Circ Arrhythm Electrophysiol. 2016 Apr;9(4):e003439. doi: 10.1161/CIRCEP.115.003439. PubMed PMID: 27071825.

Equilibrium and kinetic selectivity profiling on the human adenosine receptors.
Guo D, Dijksteel GS, van Duijl T, Heezen M, Heitman LH, IJzerman AP.
Biochem Pharmacol. 2016 Apr 1;105:34-41. doi: 10.1016/j.bcp.2016.02.018. PubMed PMID: 26930564.

Analysis of Iterative Screening with Stepwise Compound Selection Based on Novartis In-house HTS Data.
Paricharak S, IJzerman AP, Bender A, Nigsch F.
ACS Chem Biol. 2016 May 20;11(5):1255-64. doi: 10.1021/acschembio.6b00029. PubMed PMID: 26878899.

Human G protein-coupled receptor studies in Saccharomyces cerevisiae.
Liu R, Wong W, IJzerman AP.
Biochem Pharmacol. 2016 Aug 15;114:103-15. doi: 10.1016/j.bcp.2016.02.010. Review. PubMed PMID: 26920251. 

Molecular Basis of Ligand Dissociation from the Adenosine A2A Receptor.
Guo D, Pan AC, Dror RO, Mocking T, Liu R, Heitman LH, Shaw DE, IJzerman AP.
Mol Pharmacol. 2016 May;89(5):485-91. doi: 10.1124/mol.115.102657. PubMed PMID: 26873858.

Getting from A to B-exploring the activation motifs of the class B adhesion G protein-coupled receptor subfamily G member 4/GPR112.
Peeters MC, Mos I, Lenselink EB, Lucchesi M, IJzerman AP, Schwartz TW.
FASEB J. 2016 May;30(5):1836-48. doi: 10.1096/fj.201500110. PubMed PMID: 26823453.

Persistent GnRH receptor activation in pituitary αT3-1 cells analyzed with a label-free technology.
Nederpelt I, Vergroesen RD, IJzerman AP, Heitman LH.
Biosens Bioelectron. 2016 May 15;79:721-7. doi: 10.1016/j.bios.2015.12.066. PubMed PMID: 26774084.

The role of the C-terminus of the human hydroxycarboxylic acid receptors 2 and 3 in G protein activation using Gα-engineered yeast cells.
Liu R, van Veldhoven JP, IJzerman AP.
Eur J Pharmacol. 2016 Jan 5;770:70-7. doi: 10.1016/j.ejphar.2015.11.052. PubMed PMID: 26656756.

Scintillation proximity assay (SPA) as a new approach to determine a ligand's kinetic profile. A case in point for the adenosine A1 receptor.
Xia L, de Vries H, IJzerman AP, Heitman LH.
Purinergic Signal. 2016 Mar;12(1):115-26. doi: 10.1007/s11302-015-9485-0. PubMed PMID: 26647040; PubMed Central PMCID:PMC4749533.

Molecular mechanism of positive allosteric modulation of the metabotropic glutamate receptor 2 by JNJ-46281222.
Doornbos ML, Pérez-Benito L, Tresadern G, Mulder-Krieger T, Biesmans I, Trabanco AA, Cid JM, Lavreysen H, IJzerman AP, Heitman LH. Br J Pharmacol. 2016 Feb;173(3):588-600. doi: 10.1111/bph.13390.
PubMed PMID: 26589404; PubMed Central PMCID: PMC4728424.


Publications 2015


Alexander SP, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson

AJ, Sharman JL, Southan C, Buneman OP, Catterall WA, Cidlowski JA, Davenport AP,

Fabbro D, Fan G, McGrath JC, Spedding M, Davies JA; CGTP Collaborators.. The

Concise Guide to PHARMACOLOGY 2015/16: Overview. Br J Pharmacol. 2015

Dec;172(24):5729-43. doi: 10.1111/bph.13347. PubMed PMID: 26650438; PubMed

Central PMCID: PMC4718217.


Yu Z, van Veldhoven JP, 't Hart IM, Kopf AH, Heitman LH, IJzerman AP.

Synthesis and biological evaluation of negative allosteric modulators of the

Kv11.1(hERG) channel. Eur J Med Chem. 2015 Dec 1;106:50-9. doi:

10.1016/j.ejmech.2015.10.032. PubMed PMID: 26519929.



Guo D, Heitman LH, IJzerman AP. The Role of Target Binding Kinetics in Drug

Discovery. ChemMedChem. 2015 Nov;10(11):1793-6. doi: 10.1002/cmdc.201500310.

PubMed PMID: 26506404.



Massink A, Holzheimer M, Hölscher A, Louvel J, Guo D, Spijksma G, Hankemeier

T, IJzerman AP. Mass spectrometry-based ligand binding assays on adenosine A1 and

A2A receptors. Purinergic Signal. 2015 Dec;11(4):581-94. doi:

10.1007/s11302-015-9477-0. PubMed PMID: 26482925; PubMed Central PMCID:




Nederpelt I, Georgi V, Schiele F, Nowak-Reppel K, Fernández-Montalván AE,

IJzerman AP, Heitman LH. Characterization of 12 GnRH peptide agonists - a kinetic

perspective. Br J Pharmacol. 2016 Jan;173(1):128-41. doi: 10.1111/bph.13342.

PubMed PMID: 26398856; PubMed Central PMCID: PMC4813373.



Peeters MC, Fokkelman M, Boogaard B, Egerod KL, van de Water B, IJzerman AP,

Schwartz TW. The adhesion G protein-coupled receptor G2 (ADGRG2/GPR64)

constitutively activates SRE and NFκB and is involved in cell adhesion and

migration. Cell Signal. 2015 Dec;27(12):2579-88. doi:

10.1016/j.cellsig.2015.08.015. PubMed PMID: 26321231.



Louvel J, Guo D, Soethoudt M, Mocking TA, Lenselink EB, Mulder-Krieger T,

Heitman LH, IJzerman AP. Structure-kinetics relationships of Capadenoson

derivatives as adenosine A1 receptor agonists. Eur J Med Chem. 2015 Aug

28;101:681-91. doi: 10.1016/j.ejmech.2015.07.023. PubMed PMID: 26210506.



Hillger JM, Schoop J, Boomsma DI, Slagboom PE, IJzerman AP, Heitman LH.

Whole-cell biosensor for label-free detection of GPCR-mediated drug responses in

personal cell lines. Biosens Bioelectron. 2015 Dec 15;74:233-42. doi:

10.1016/j.bios.2015.06.031. PubMed PMID: 26143464.



Romagnoli R, Baraldi PG, Lopez-Cara C, Cruz-Lopez O, Moorman AR, Massink A,

IJzerman AP, Vincenzi F, Borea PA, Varani K. Synthesis and biological evaluation

of a new series of 2-amino-3-aroyl thiophene derivatives as agonist allosteric

modulators of the A1 adenosine receptor. A position-dependent effect study. Eur J

Med Chem. 2015 Aug 28;101:185-204. doi: 10.1016/j.ejmech.2015.06.041. PubMed

PMID: 26141910.



Yu Z, van Veldhoven JP, Louvel J, 't Hart IM, Rook MB, van der Heyden MA,

Heitman LH, IJzerman AP. Structure-Affinity Relationships (SARs) and

Structure-Kinetics Relationships (SKRs) of Kv11.1 Blockers. J Med Chem. 2015 Aug

13;58(15):5916-29. doi: 10.1021/acs.jmedchem.5b00518. PubMed PMID: 26125327.



Vilums M, Zweemer AJ, Dilanchian A, van Veldhoven JP, de Vries H, Brussee J,

Saunders J, Stamos D, Heitman LH, IJzerman AP. Evaluation of

(4-Arylpiperidin-1-yl)cyclopentanecarboxamides As High-Affinity and

Long-Residence-Time Antagonists for the CCR2 Receptor. ChemMedChem. 2015

Jul;10(7):1249-58. doi: 10.1002/cmdc.201500058. PubMed PMID: 26033831.



Vilums M, Heuberger J, Heitman LH, IJzerman AP. Indanes--Properties,

Preparation, and Presence in Ligands for G Protein Coupled Receptors. Med Res

Rev. 2015 Nov;35(6):1097-126. doi: 10.1002/med.21352. Review. PubMed PMID:




Paricharak S, Cortés-Ciriano I, IJzerman AP, Malliavin TE, Bender A.

Proteochemometric modelling coupled to in silico target prediction: an integrated

approach for the simultaneous prediction of polypharmacology and binding

affinity/potency of small molecules. J Cheminform. 2015 Apr 15;7:15. doi:

10.1186/s13321-015-0063-9. PubMed PMID: 25926892; PubMed Central PMCID:




Liu R, Nahon D, le Roy B, Lenselink EB, IJzerman AP. Scanning mutagenesis in

a yeast system delineates the role of the NPxxY(x)(5,6)F motif and helix 8 of the

adenosine A(2B) receptor in G protein coupling. Biochem Pharmacol. 2015 Jun

15;95(4):290-300. doi: 10.1016/j.bcp.2015.04.005. PubMed PMID: 25896847.



van Veldhoven JP, Liu R, Thee SA, Wouters Y, Verhoork SJ, Mooiman C, Louvel

J, IJzerman AP. Affinity and kinetics study of anthranilic acids as HCA2 receptor

agonists. Bioorg Med Chem. 2015 Jul 15;23(14):4013-25. doi:

10.1016/j.bmc.2015.02.018. PubMed PMID: 25737085.



Li P, Rial D, Canas PM, Yoo JH, Li W, Zhou X, Wang Y, van Westen GJ, Payen

MP, Augusto E, Gonçalves N, Tomé AR, Li Z, Wu Z, Hou X, Zhou Y, IJzerman AP,

Boyden ES, Cunha RA, Qu J, Chen JF. Optogenetic activation of intracellular

adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB

phosphorylation and impair memory. Mol Psychiatry. 2015 Nov;20(11):1339-49. doi:




Vilums M, Zweemer AJ, Barmare F, van der Gracht AM, Bleeker DC, Yu Z, de

Vries H, Gross R, Clemens J, Krenitsky P, Brussee J, Stamos D, Saunders J,

Heitman LH, IJzerman AP. When structure-affinity relationships meet

structure-kinetics relationships:

3-((Inden-1-yl)amino)-1-isopropyl-cyclopentane-1-carboxamides as CCR2

antagonists. Eur J Med Chem. 2015 Mar 26;93:121-34. doi:

10.1016/j.ejmech.2015.01.063. PubMed PMID: 25666912.



Massink A, Gutiérrez-de-Terán H, Lenselink EB, Ortiz Zacarías NV, Xia L,

Heitman LH, Katritch V, Stevens RC, IJzerman AP. Sodium ion binding pocket

mutations and adenosine A2A receptor function. Mol Pharmacol. 2015

Feb;87(2):305-13. doi: 10.1124/mol.114.095737. PubMed PMID: 25473121.

Yu Z, IJzerman AP, Heitman LH. Kv 11.1 (hERG)-induced cardiotoxicity: a

molecular insight from a binding kinetics study of prototypical Kv 11.1 (hERG)

inhibitors. Br J Pharmacol. 2015 Feb;172(3):940-55. doi: 10.1111/bph.12967.

PubMed PMID: 25296617; PubMed Central PMCID: PMC4301700.


Publications 2014


Vilums M, Zweemer AJ, Dekkers S, Askar Y, de Vries H, Saunders J, Stamos D,

Brussee J, Heitman LH, IJzerman AP. Design and synthesis of novel small molecule

CCR2 antagonists: evaluation of 4-aminopiperidine derivatives. Bioorg Med Chem

Lett. 2014 Dec 1;24(23):5377-80. PubMed PMID: 25453791.



Bansal M, Yang J, Karan C, Menden MP, Costello JC, Tang H, Xiao G, Li Y,

Allen J, Zhong R, Chen B, Kim M, Wang T, Heiser LM, Realubit R, Mattioli M,

Alvarez MJ, Shen Y; NCI-DREAM Community., Gallahan D, Singer D, Saez-Rodriguez J,

Xie Y, Stolovitzky G, Califano A; NCI-DREAM Community.. A community computational

challenge to predict the activity of pairs of compounds. Nat Biotechnol. 2014

Dec;32(12):1213-22. doi: 10.1038/nbt.3052. PubMed PMID: 25419740; PubMed Central

PMCID: PMC4399794.



Cohen S, Barer F, Bar-Yehuda S, IJzerman AP, Jacobson KA, Fishman P. A₃

adenosine receptor allosteric modulator induces an anti-inflammatory effect: in

vivo studies and molecular mechanism of action. Mediators Inflamm.

2014;2014:708746. doi: 10.1155/2014/708746. PubMed PMID: 25374446; PubMed Central

PMCID: PMC4211160.


van Diepen HC, Lucassen EA, Yasenkov R, Groenen I, Ijzerman AP, Meijer JH,

Deboer T. Caffeine increases light responsiveness of the mouse circadian

pacemaker. Eur J Neurosci. 2014 Nov;40(10):3504-11. doi: 10.1111/ejn.12715.

PubMed PMID: 25196050.



Romagnoli R, Baraldi PG, IJzerman AP, Massink A, Cruz-Lopez O, Lopez-Cara LC,

Saponaro G, Preti D, Aghazadeh Tabrizi M, Baraldi S, Moorman AR, Vincenzi F,

Borea PA, Varani K. Synthesis and biological evaluation of novel allosteric

enhancers of the A1 adenosine receptor based on

2-amino-3-(4'-chlorobenzoyl)-4-substituted-5-arylethynyl thiophene. J Med Chem.

2014 Sep 25;57(18):7673-86. doi: 10.1021/jm5008853. PubMed PMID: 25181013.



Peeters MC, Li Q, Elands R, van Westen GJ, Lenselink EB, Müller CE, IJzerman

AP. Domains for activation and inactivation in G protein-coupled receptors--a

mutational analysis of constitutive activity of the adenosine A2B receptor.

Biochem Pharmacol. 2014 Nov 15;92(2):348-57. doi: 10.1016/j.bcp.2014.08.022.

PubMed PMID: 25179146.



Guo D, Venhorst SN, Massink A, van Veldhoven JP, Vauquelin G, IJzerman AP,

Heitman LH. Molecular mechanism of allosteric modulation at GPCRs: insight from a

binding kinetics study at the human A1 adenosine receptor. Br J Pharmacol. 2014

Dec;171(23):5295-312. doi: 10.1111/bph.12836. PubMed PMID: 25040887; PubMed

Central PMCID: PMC4294041.



Zweemer AJ, Bunnik J, Veenhuizen M, Miraglia F, Lenselink EB, Vilums M, de

Vries H, Gibert A, Thiele S, Rosenkilde MM, IJzerman AP, Heitman LH. Discovery

and mapping of an intracellular antagonist binding site at the chemokine receptor

CCR2. Mol Pharmacol. 2014 Oct;86(4):358-68. doi: 10.1124/mol.114.093328. PubMed

PMID: 25024169.



Costello JC, Heiser LM, Georgii E, Gönen M, Menden MP, Wang NJ, Bansal M,

Ammad-ud-din M, Hintsanen P, Khan SA, Mpindi JP, Kallioniemi O, Honkela A,

Aittokallio T, Wennerberg K; NCI DREAM Community., Collins JJ, Gallahan D, Singer

D, Saez-Rodriguez J, Kaski S, Gray JW, Stolovitzky G. A community effort to

assess and improve drug sensitivity prediction algorithms. Nat Biotechnol. 2014

Dec;32(12):1202-12. doi: 10.1038/nbt.2877. PubMed PMID: 24880487; PubMed Central

PMCID: PMC4547623.



Lenselink EB, Beuming T, Sherman W, van Vlijmen HW, IJzerman AP. Selecting an

optimal number of binding site waters to improve virtual screening enrichments

against the adenosine A2A receptor. J Chem Inf Model. 2014 Jun 23;54(6):1737-46.

doi: 10.1021/ci5000455. PubMed PMID: 24835542.



Zweemer AJ, Toraskar J, Heitman LH, IJzerman AP. Bias in chemokine receptor

signalling. Trends Immunol. 2014 Jun;35(6):243-52. doi: 10.1016/j.it.2014.02.004.

Review. PubMed PMID: 24679437.



Louvel J, Guo D, Agliardi M, Mocking TA, Kars R, Pham TP, Xia L, de Vries H,

Brussee J, Heitman LH, Ijzerman AP. Agonists for the adenosine A1 receptor with

tunable residence time. A Case for nonribose

4-amino-6-aryl-5-cyano-2-thiopyrimidines. J Med Chem. 2014 Apr 24;57(8):3213-22.

doi: 10.1021/jm401643m. PubMed PMID: 24669958.



Guo D, Xia L, van Veldhoven JP, Hazeu M, Mocking T, Brussee J, Ijzerman AP,

Heitman LH. Binding kinetics of ZM241385 derivatives at the human adenosine A2A

receptor. ChemMedChem. 2014 Apr;9(4):752-61. doi: 10.1002/cmdc.201300474. PubMed

PMID: 24591302.



Guo D, Hillger JM, IJzerman AP, Heitman LH. Drug-target residence time--a

case for G protein-coupled receptors. Med Res Rev. 2014 Jul;34(4):856-92. doi:

10.1002/med.21307. Review. PubMed PMID: 24549504.



Liu R, Groenewoud NJ, Peeters MC, Lenselink EB, IJzerman AP. A yeast

screening method to decipher the interaction between the adenosine A2B receptor

and the C-terminus of different G protein α-subunits. Purinergic Signal. 2014

Sep;10(3):441-53. doi: 10.1007/s11302-014-9407-6. PubMed PMID: 24464644; PubMed

Central PMCID: PMC4152457.



Koutsoukas A, Paricharak S, Galloway WR, Spring DR, Ijzerman AP, Glen RC,

Marcus D, Bender A. How diverse are diversity assessment methods? A comparative

analysis and benchmarking of molecular descriptor space. J Chem Inf Model. 2014

Jan 27;54(1):230-42. doi: 10.1021/ci400469u. PubMed PMID: 24289493.



Yu Z, Klaasse E, Heitman LH, Ijzerman AP. Allosteric modulators of the hERG

K(+) channel: radioligand binding assays reveal allosteric characteristics of

dofetilide analogs. Toxicol Appl Pharmacol. 2014 Jan 1;274(1):78-86. doi:

10.1016/j.taap.2013.10.024. PubMed PMID: 24200993.


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