Computational medicinal chemistry group

Chris de Graaf

last update: April 2015

Piet Mondrian - Boogie-Woogie








Conformational states of the full-length glucagon receptor

Yang L, Yang D, de Graaf C, Moeller A, West GM, Dharmarajan V, Wang C, Siu FY, Song G, Reedtz-Runge S, Pascal BD, Wu B, Potter CS, Zhou H, Griffin PR, Carragher B, Yang H, Wang MW, Stevens RC, Jiang H
Nature Communications 2015, 6, 7859, doi:10.1038/ncomms8859

A Molecular Pharmacologist's Guide to G Protein-Coupled Receptor Crystallography

Piscitelli CL, Kean J, de Graaf C, Deupi X
Mol Pharmacol. 2015, 88: 536-551. doi:10.1124/mol.115.099663

Structure-Based Prediction of GPCR-Ligand Function: A β-adrenoceptor Case Study

Kooistra AJ, Leurs R, de Esch IJP, de Graaf C
J Chem Info Model 2015, 55:1045-1061, doi:10.1021/acs.jcim.5b00066

Combinatorial Consensus Scoring for Ligand-Based Virtual Fragment Screening: A Comparative Case Study for Serotonin 5-HT3A, Histamine H1 and Histamine H4 Receptors

Schultes S, Kooistra AJ, Vischer HF, Nijmeijer S, Haaksma EE, Leurs R, de Esch IJP, de Graaf C
J Chem Info Model 2015, 55: 1033-1040, doi: 10.1021/ci500694c

Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H4 receptor

Istyastono EP, Kooistra AJ, Vischer HF, Kuijer M, Roumen L, Nijmeijer S, Smits RA, de Esch IJP, Leurs R, de Graaf C
MedChemComm doi: 10.1039/C5MD00022J

Analyzing multitarget activity landscapes using protein-ligand interaction fingerprints: interaction cliffs

Méndez-Lucio O, Kooistra AJ, de Graaf C, Bender A, Medina-Franco JL
J Chem Inf Model. 2015, 55: 251-262

Generic GPCR residue numbers - aligning topology maps while minding the gaps

Isberg V, de Graaf C, Bortolato A, Cherezov V, Katritch V, Marshall FH, Mordalski S, Pin JP, Stevens RC, Vriend G, Gloriam DE
Trends Pharmacol Sci. 2015, 36: 22-31

Exploring the CXCR3 Chemokine Receptor with Small-Molecule Antagonists and Agonists

Wijtmans M, Scholten DJ, Wouter Mooij, Martine J Smit, Iwan JP de Esch, Chris de Graaf C, Leurs R
Topics in Medicinal Chemistry 2015, 14: 119-185

The Viral G Protein-Coupled Receptor ORF74 Hijacks β-Arrestins for Endocytic Trafficking in Response to Human Chemokines

de Munnik SM; Kooistra AJ; van Offenbeek J; Nijmeijer S; de Graaf C; Martine J Smit, Leurs R, Vischer HF
PLoSOne 10, e0124486


Insights into the structure of class B GPCRs.

Hollenstein K, de Graaf C, Bortolato A, Wang M-W, Marshall FH, Stevens RC
Tr Pharmacol Sci 2014, 35: 12-22

Identification of Overlapping but Differential Binding Sites for the High-Affinity CXCR3 Antagonists NBI-74330 and VUF11211.

Scholten DJ, Roumen L, Wijtmans M, Verkade-Vreeker MC, Custers H, Lai M, de Hooge D, Canals M, de Esch IJ, Smit MJ, de Graaf C, Leurs R
Mol Pharmacol 2014, 85: 116-126

From Three-Dimensional GPCR Structure to Rational Ligand Discovery

Kooistra AJ, Leurs R, de Esch IJP, de Graaf C
Adv Exp Med Biol 2014, 796: 129-157

The Receptor Concept in 3D: From Hypothesis and Metaphor to GPCR–Ligand Structures

Kooistra AJ, de Graaf C, Timmerman H
J Neurochem Res. 39: 1850-1861

A Gold Coordination Compound as a Chemical Probe to Unravel Aquaporin‐7 Function

Madeira A, de Almeida A, de Graaf C, Camps M, Zorzano A, Moura TF, Casini A, Soveral G
ChemBioChem 15: 1487-1494


Structure of the human glucagon class B G-protein-coupled receptor.

Siu FY, He M, de Graaf C, Han GW, Yang D, Zhang Z, Zhou C, Xu Q, Wacker D, Joseph JS, Liu W, Lau J, Cherezov V, Katritch V, Wang M-W, Stevens RC.
Nature 2013, 499: 444-449

Nature Reviews Drug Discovery Research Highlight

Small and colorful stones make beautiful mosaics: Fragment-Based Chemogenomics.

de Graaf C, Vischer HF, de Kloe GE, Kooistra AJ, Nijmeijer S, Martien Kuijer M, Verheij MHP, England P, van Muijlwijk-Koezen JE, Leurs R, de Esch IJP.
Drug Discov Today 2013, 18: 323-330
Practical Fragments blog

Combining quantum mechanical ligand conformation analysis and protein modeling to elucidate GPCR–ligand binding modes.

Schultes S, Engelhardt H, Roumen L, Zuiderveld OP, Haaksma EEJ, de Esch IJP, Leurs R, de Graaf C
ChemMedChem 2013, 8: 49-53

From Heptahelical Bundle to Hits from the Haystack: Structure-Based Virtual Screening for GPCR Ligands.

Kooistra AJ, Roumen L, Leurs R, de Esch IJP, de Graaf C
Meth Enzymol 2013, 522: 279–336

Detailed analysis of biased histamine H4 receptor signalling by JNJ 7777120 analogues

Nijmeijer S, Vischer HF, Sirci F, Schultes S, Engelhardt H, de Graaf C, Rosethorne E, Charlton S, Leurs R
Br J Pharmacol 2013, doi: 10.1111/bph.12117

Bispyrimidines as potent histamine H4 receptor ligands: delineation of structure activity relationships and detailed H4 receptor binding mode

Engelhardt H, Schultes S, de Graaf C, Nijmeijer S, Vischer HF,; Zuiderveld OP, Dobler J, Stachurski K, Mayer M, Arnhof H, Scharn D, Haaksma EEJ, de Esch IJP; Leurs R
J Med Chem 2013, doi: 10.1021/jm301886t

Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure

Jansen C, Wang H, Kooistra AJ, de Graaf C, Orrling K, Tenor H, Seebeck T, Bailey D, de Esch IJP, Ke H, Leurs R
J Med Chem 2013, 56: 2087-2096


Virtual fragment screening: Discovery of histamine H3 receptor ligands using ligand-based and protein-based molecular fingerprints.

Sirci F, Istyastono EP, Vischer HF, Kooistra AJ, Nijmeijer S, Kuijer M, Wijtmans M, Mannhold R, Leurs R, de Esch IJP, de Graaf C.
J Chem Info Model 2012, DOI: 10.1021/ci3004094

Diazepam-bound structure of the GABAA receptor identifies novel ligands for the benzodiazepine binding site.

Richter L, de Graaf C, Sieghart W, Varagic, Z, Mörzinger, M, de Esch IJP, Ecker GF, Ernst M.
Nat Chem Biol 2012, 8: 455-464
Interview Dutch Radio

Chemical subtleties in small-molecule modulation of peptide receptor function: The case of CXCR3 biaryl-type ligands.

Wijtmans M, Scholten DJ, Roumen L, Canals M, Custer H, Glas M, Vreeker MCA, de Kanter FJJ, de Graaf C, Smit MJ, de Esch IJP, Leurs R.
J Med Chem 2012, 55: 10572–10583

Mapping histamine H4 receptor-ligand binding modes.

Schultes S, Nijmeijer S, Engelhardt H, Kooistra AJ, Vischer HF, de Esch IJP, Haaksma EJ, Leurs R, de Graaf C
MedChemComm 2012, 4: 193-204
Themed Issue Highlighting New Talent In Medicinal Chemistry

A Prospective Cross-Screening Study on G Protein-Coupled Receptors: Lessons Learned in Virtual Compound Library Design.

Sanders MPA, Roumen L, van der Horst E, Lane JR, Vischer HF, van Offenbeek J, de Vries H, Verhoeven S, Chow KY, Verkaar F, Beukers MW, McGuire R, Leurs R, IJzerman AP, de Vlieg J, de Esch IJP, Zaman GJ, Klomp JPG, Bender A, de Graaf C.
J Med Chem 2012, 55: 5311-5325

C(X)CR in silico: Computer-aided prediction of chemokine receptor-ligand interactions.

Roumen, L, Scholten, DJ, de Kruijf, P, de Esch, IJP, Leurs, R, de Graaf, C.
Drug Discov Today: Technologies 2012, DOI: 10.1016/j.ddtec.2012.05.002

From the Protein’s Perspective: The Benefits and Challenges of Protein Structure-Based Pharmacophore Modeling.

Sanders MPA, McGuire R, Roumen L, de Esch IJP, de Vlieg J, Klomp J, de Graaf C.
MedChemComm 2012, 3: 28-38
(highlighted on MedChemComm blog)

The application of unnatural amino acids to chemokine receptor research.

Siderius M, Wal M, Scholten DJ, Smit MJ, Sakmar T, Leurs R, de Graaf C.
Drug Discov Today: Technologies 2012, DOI: 10.1016/j.ddtec.2012.07.008.

Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain.

Akdemir A, Edink ES, Thompson AJ, Lummis SCR, Kooistra AJ, de Graaf C, de Esch IJP.
Bioorg Med Chem 2012, DOI: 10.1016/j.bmc.2012.06.054

Medicinal chemistry perspective on melting point: matched molecular pair analysis of the effects of simple descriptors on the melting point of drug-like compounds.

Schultes S, de Graaf C, Berger H, Mayer M, Steffen A, Haaksma EEJ, de Esch IJP, Leurs R, Krämer OA.
MedChemComm 2012 3: 584-591

Biochemical and pharmacological characterization of the histamine H4 receptor.

Nijmeijer S, de Graaf, C, Leurs R, Vischer HF
Front Biosci 2012, 17, 2089-2106

Pharmacological Modulation of Chemokine Receptor Function.

Scholten D, Canals M, Maussang D, Roumen L, Smit M, Wijtmans M, de Graaf C, Vischer H, Leurs R
Br J Pharmacol 2012, 165: 1617-1643

Design and pharmacological characterization of VUF14480, a covalent partial agonist that interacts with cysteine 98 of the human histamine H4 receptor.

Nijmeijer S, Engelhardt H, Schultes S, Van de Stolpe A, Lusink V, de Graaf C, Wijtmans M, Haaksma EE, de Esch IJP, Stachurski K, Vischer H, Leurs R
Br J Pharmacol 2012, In press

Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists.

Wijtmans M, Maussang D, Sirci F, Delic A, Chong M, Chatalic K, Custers H, Jansen E, de Graaf C, Smit M, de Esch IJP, Leurs R
Eur J Med Chem 2012, 51: 184-192


Crystal structure-based virtual screening for novel fragment-like ligands of the human histamine H1 receptor.

de Graaf C, Kooistra AJ, Vischer HF, Katritch, V, Kuijer M, Shiroishi M, Shimamura T, Iwata S, Stevens RC, de Esch IJP, Leurs R
J Med Chem 2011, 54: 8195-8206
Recommended by Faculty of 1000 (F1000Prime)

Molecular determinants of ligand binding modes in the histamine H4 receptor: Linking ligand-based 3D-QSAR models to in silico guided receptor mutagenesis studies.

Istyastono EP, Nijmeijer S, Lim HD, van de Stolpe A, Roumen L, Kooistra AJ, Vischer H, de Esch IJP, Leurs R, de Graaf C
J Med Chem 2011, 54: 8136-8147

In Silico Veritas: The Pitfalls and Challenges of Predicting GPCR-Ligand Interactions.

Roumen L, Sanders MPA, Vroling B, de Esch IJP, De Vlieg J, Leurs R, Klomp J, Nabuurs SB, de Graaf C
Pharmaceuticals 4, 1196-1215.

Snooker: A structure based pharmacophore generation tool applied to class A GPCRs.

Sanders M, Verhoeven S, de Graaf C, Roumen L, de Vlieg J, Klomp J
J Chem Info Model 2011, 51: 2277-2292

Fragment library screening reveals remarkable similarities between histamine H4 receptors and serotonin 5-HT3 receptors.

Verheij MHP, de Graaf C, de Kloe GE, Nijmeijer S, Vischer H, Smits RA, Zuiderveld, O, Thompson AJ, van Muijlwijk-Koezen JE, Lummis SC, Leurs R, IJP de Esch
Bioorg Med Chem Lett 2011, 21, 5460-5464

Status of GPCR Modeling and Docking as Reflected by Community-wide GPCR Dock 2010 Assessment.

Kufareva I, Rueda M, Katritch V, GPCR Dock 2010 participants {Roumen, L, de Esch, IJP, Leurs, R, de Graaf, C}, Stevens RC, Abagyan R
Structure 2011 19:1108-26
VU-MedChem team winner of GPCR DOCK 2010 CXCR4-ligand modeling competition

Triazole ligands reveal distinct molecular features that induce H4R affinity and subtly govern H4R/H3R selectivity.

Wijtmans M, de Graaf C, de Kloe GE, Istyastono EP, Boonnak R, Jongejan A, Zuiderveld O, de Esch IJP, Leurs R
J Med Chem 2011, 54: 1693-1703

Identification of a novel allosteric binding site in the CXCR2 chemokine receptor.

de Kruijf P, Lim HD, Roumen L, Renjaan VA, Zhao J, Webb ML, Auld DA, Wijkmans JCHM, Zaman GJR, Smit MJ, de Graaf C, Leurs R
Mol Pharmacol 80: 1108-1118

Molecular determinants of selective agonist and antagonist binding to the histamine H4 receptor.

Istyastono EP, de Graaf C, de Esch IJP, Leurs R
Curr Top Med Chem 2011, 11: 661-679

Agonist-dependent effects of mutations in the sphingosine-1-phosphate type 1 receptor.

de Graaf C, Van Loenen PB, Verzijl D, Leurs R, Rognan D, Peters SLM Alewijnse AE
Eur J Pharmacol 2011, 667: 105

Acetylcholine binding protein (AChBP) as template for hierarchical in silico screening procedures to identify structurally novel ligands for the nicotinic receptors.

Akdemir A, Rucktooa P, Jongejan A, Van Elk R, Bertrand S, Sixma TK, Bertrand D, Smit AB, Leurs R, de Graaf, C, de Esch IJP
Bioorg Med Chem Lett 2011, 19(20): 6107-19

Ligand efficiency as a guide in fragment hit selection and optimization.

Schultes S, de Graaf C, Haaksma EEJ, de Esch IJP, Leurs R, Krämer O
Drug Discovery Today: Technologies 2011, 7: e157-e162


Molecular determinants of ligand binding to H4R species variants.

de Graaf C, Lim HD, Jiang W, Sadek P, McGovern PM, Istyastono EP, Bakker RA, de Esch IJP, Thurmond RL, Leurs R
Mol Pharmacol 2010, 77: 734-43

Electron Density Fingerprints (EDprints): Virtual Screening Using Assembled Information of Electron Density.

Kooistra AJ, Binsl TW, Van Beek JHGM, de Graaf C, Heringa J
J Chem Inf Model 2010, 50: 1772-1780

Improved inhibition of the histone acetyltransferase PCAF by an anacardic acid derivative.

Ghizzoni M, Boltjes A, de Graaf C, Haisma HJ, Dekker FJ
Bioorg Med Chem 2010, 18: 5826-5833


Increasing selectivity of CC chemokine receptor 8 antagonists by engineering nondesolvation related interactions with the intended and off-target binding sites.

Shamovsky I, de Graaf C, Alderin OL, Bengtsson M, Bladh H, Borjesson L, Connolly S, Dyke HJ, van den Heuvel M, Johansson H, Josefsson B-G, Kristoffersson A, Linnanen T, Lisius A, Mannikko R, Norden B, Price S, Ripa L, Rognan D, Rosendahl A, Skrinjar M, Urbahns K
J Med Chem 2009, 52: 7706-7723
Special Journal of Medicinal Chemistry Centennial issue

Customizing G Protein-Coupled Receptor Models for Structure-Based Virtual Screening.

de Graaf C, Rognan D
Curr Pharm Des 2009 15: 4026-4048

Conformationally constrained opioid ligands: the Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold.

Ballet S, Feytens D, Wachter RD, Vlaeminck MD, Marczak ED, Salvadori S, de Graaf C, Rognan D, Negri L, Lattanzi R, Lazarus LH, Tourwé D, Balboni G
Bioorg Med Chem Lett 2009, 19: 433-437


Cytochrome P450 protein modeling and ligand docking.

Feenstra KA, de Graaf C, Vermeulen NPE
In: Drug-drug interactions, 2nd edition 2008, Ed D Rodrigues, CRC Press, p 435-470

Free energies of binding of R- and S- propranolol to wildtype and mutant Cytochrome P450 2D6 from molecular dynamics simulations.

C de Graaf, C Oostenbrink, PHJ Keizers, BMA Van Vugt-Lussenburg, NPE Vermeulen
Eur Biophys J 2007, 36: 589-599

Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: a spectroscopic and computational study.

Bonifacio A, Groenhof AR, Keizers PHJ, de Graaf C, Commandeur JNM, Vermeulen NPE, Ehlers AW, Lammertsma K, Gooijer C, van der Zwan G
J Biol Inorg Chem 2007, 12: 645-654

Molecular modeling guided site-directed mutagenesis of cytochrome P450 2D6.

de Graaf C, Oostenbrink C, Keizers PHJ, Van Vugt-Lussenburg BMA, van Waterschoot RAB, Tschirret-Guth RA, Commandeur JNM, Vermeulen NPE
Curr Drug Metab 2007, 8: 59-77

Metabolism of N-substituted 7-methoxy-4-(aminomethyl)-coumarins by cytochrome P450 2D6 mutants indicates additional substrate interaction points.

Keizers PHJ, van Dijk BR, de Graaf C, Vugt-Lussenburg BMA, Vermeulen NPE, Commandeur JNM
Xenobiotica 2006, 36: 763-771

Topological role of cytochrome P450 2D6 active site residues.

RAB van Waterschoot, PHJ Keizers, C de Graaf, NPE Vermeulen and RA Tschirret-Guth
Arch Biochem Biophys 2006, 447: 53-58

Catalytic site prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking.

de Graaf C, Oostenbrink C, Keizers PHJ, van der Wijst T, Jongejan A, Vermeulen NPE
J Med Chem 2006, 49: 2417-2430

Binding of 7-methoxy-4-(aminomethyl)-coumarin to wild-type and W128F mutant cytochrome P450 2D6 studied by time-resolved fluorescence spectroscopy.

Stortelder A, Keizers PHJ, Oostenbrink C, de Graaf C, de Kruijf P, Vermeulen NPE, Gooijer C, Commandeur JNM, van der Zwan G
Biochem J 2006, 393: 635-643

Role of the conserved threonine 309 in mechanism of oxidation by cytochrome P450 2D6.

Keizers PHJ, Schraven LH, de Graaf C, Hidestrand M, Ingelman-Sundberg M, Vermeulen NPE, Commandeur JNM
Biochem Biophys Res Commun 338 (2005) 1065-1074

Metabolic regio- and stereoselectivity of cytochrome P450 2D6 towards 3,4-methylenedioxy-N-alkylamphetamines: in silico predictions and experimental validation.

C de Graaf, PHJ Keizers, FJ de Kanter, C Oostenbrink, KA Feenstra, JNM Commandeur, Vermeulen NPE
J Med Chem 2005, 48: 6117-6127

Cytochrome P450 in silico: an integrative modeling approach.

de Graaf, C, Vermeulen NPE, Feenstra KA
J Med Chem 48 (2005) 2725-2755

The role of phenylalanine 483 in cytochrome P450 2D6 is strongly substrate dependent.

Lussenburg BMA, Keizers PHJ, de Graaf C, Hidestrand M, Ingelman-Sundberg M, Vermeulen NPE, Commandeur JNM
Biochem Pharmacol 2005, 70: 1253-1261

The role and application of in silico docking in chemical genomics research.

Jongejan A, de Graaf C, Vermeulen NPE, Leurs R, de Esch IJP
Methods Mol Biol 2005, 310: 63-91

Influence of phenylalanine 120 on cytochrome P450 2D6 catalytic selectivity and regiospecificity: crucial role in 7-methoxy-4-(aminomethyl)-coumarin metabolism.

Keizers PHJ, Lussenburg BMA, de Graaf C, Mentink LM, Vermeulen NPE, Commandeur JNM
Biochem Pharmacol 2004, 68: 2263-2271


Fate modeling of nonylphenol ethoxylates and their metabolites in the Dutch Scheldt and Rhine estuaries: validation with new field data.

Jonkers N, Laane RWPM, de Graaf C, de Voogt P
Estuarine Coastal and Shelf Science 2005, 62: 141-160

2012© Daphné Truan