Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds

Targeting Protein Multiple Conformations: A Structure-Based Strategy for Kinase Drug Design

Jeffrey, L., & Robert, A. (2007) · Current Topics in Medicinal Chemistry · doi:10.2174/156802607781696783 · Cited by 37

Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology

Schierle, S., Flauaus, C., Heitel, P., Willems, S., Schmidt, J., Kaiser, A., Weizel, L., Goebel, T., Kahnt, A. S., Geißlinger, G., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00458 · Cited by 37

Low-dose drug combinations along molecular pathways could maximize therapeutic effectiveness while minimizing collateral adverse effects

Lötsch, J., & Geißlinger, G. (2011) · Drug Discovery Today · doi:10.1016/j.drudis.2011.10.003 · Cited by 36

Polypharmacology of Approved Anticancer Drugs

Amelio, I., Lisitsa, A., Knight, R. A., Melino, G., & Antonov, A. V. (2016) · Current Drug Targets · doi:10.2174/1389450117666160301095233 · Cited by 36

Animal models of l-DOPA-induced dyskinesia: the 6-OHDA-lesioned rat and mouse

Tronci, E., & Francardo, V. (2017) · Journal of Neural Transmission · doi:10.1007/s00702-017-1825-5 · Cited by 36

Structure-activity studies on N -Substituted tranylcypromine derivatives lead to selective inhibitors of lysine specific demethylase 1 (LSD1) and potent inducers of leukemic cell differentiation

Schulz‐Fincke, J., Hau, M., Barth, J., Robaa, D., Willmann, D., Kürner, A., Haas, J., Greve, G., Haydn, T., Fulda, S., et al. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.12.001 · Cited by 36

New drugs in psychiatry: focus on new pharmacological targets

Caraci, F., Leggio, G. M., Salomone, S., & Drago, F. (2017) · F1000Research · doi:10.12688/f1000research.10233.1 · Cited by 35

In silico identification of drug target pathways in breast cancer subtypes using pathway cross-talk inhibition

Cava, C., Bertoli, G. R., & Castiglioni, I. (2018) · Journal of Translational Medicine · doi:10.1186/s12967-018-1535-2 · Cited by 35

Designing Multitarget Anti‐inflammatory Agents: Chemical Modulation of the Lumiracoxib Structure toward Dual Thromboxane Antagonists–COX‐2 Inhibitors

Bertinaria, M., Shaikh, M. A., Buccellati, C., Cena, C., Rolando, B., Lazzarato, L., Fruttero, R., Gasco, A., Hoxha, M., Capra, V., et al. (2012) · ChemMedChem · doi:10.1002/cmdc.201200272 · Cited by 32

Synthesis and Structure–Activity Relationship Studies of Derivatives of the Dual Aromatase–Sulfatase Inhibitor 4‐{[(4‐Cyanophenyl)(4H‐1,2,4‐triazol‐4‐yl)amino]methyl}phenyl sulfamate

Woo, L. W. L., Wood, P. M., Bubert, C., THOMAS, M. P., Purohit, A., & Potter, B. V. L. (2013) · ChemMedChem · doi:10.1002/cmdc.201300015 · Cited by 32

A broad-spectrum lipidomics screen of antiinflammatory drug combinations in human blood

Mazaleuskaya, L. L., Lawson, J. A., Li, X., Grant, G. R., Mesaros, C., Großer, T., Blair, I. A., Ricciotti, E., & FitzGerald, G. A. (2016) · JCI Insight · doi:10.1172/jci.insight.87031 · Cited by 31

S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α2-Adrenoceptor Antagonist and Potential Antidepressant: II. A Behavioral, Neurochemical, and Electrophysiological Characterization

Dekeyne, A., Brocco, M., Loiseau, F., Gobert, A., Rivet, J., Cara, B. D., Cremers, T. I. F. H., Flik, G., Fone, K. C. F., Watson, D. J., et al. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.187534 · Cited by 30

SKI-178: A multitargeted inhibitor of sphingosine kinase and microtubule dynamics demonstrating therapeutic efficacy in acute myeloid leukemia models

Yun, J., Hengst, J., Dick, T., Sharma, A. K., Doi, K., Hegde, S., Tan, S., Geffert, L., Fox, T., Sharma, A., et al. (2017) · Cancer translational medicine · doi:10.4103/ctm.ctm_7_17 · Cited by 30

Pleiotropic effects of hypoglycemic agents: implications in asthma and COPD

Rogliani, P., Ora, J., Daniele, N. D., & Lauro, D. (2018) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2018.01.002 · Cited by 30

Design, synthesis, and evaluation of imidazo[4,5-c]pyridin-4-one derivatives with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ

Casimiro‐Garcia, A., Heemstra, R. J., Bigge, C. F., Chen, J., Ciske, F. L., Davis, J. A., Ellis, T., Esmaeil, N., Flynn, D. A., Han, S., et al. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.11.088 · Cited by 28

Analyzing Multitarget Activity Landscapes Using Protein–Ligand Interaction Fingerprints: Interaction Cliffs

Méndez‐Lucio, O., Kooistra, A. J., de Graaf, C., Bender, A., & Medina‐Franco, J. L. (2015) · Journal of Chemical Information and Modeling · doi:10.1021/ci500721x · Cited by 26

Assembly/Disassembly of Drug Conjugates Using Imide Ligation

Mhidia, R., Bézière, N., Blanpain, A., Pommery, N., & Melnyk, O. (2010) · Organic Letters · doi:10.1021/ol101049g · Cited by 26

Designed multiple ligands in metabolic disease research: from concept to platform

Gattrell, W. T., Johnstone, C., Patel, S., Smith, C. S., Scheel, A. A., & Schindler, M. (2013) · Drug Discovery Today · doi:10.1016/j.drudis.2013.02.006 · Cited by 25

Characterization of New PPARγ Agonists: Benzimidazole Derivatives – the Importance of Position 2

Goebel, M., Staels, B., Unger, T., Kintscher, U., & Gust, R. (2009) · ChemMedChem · doi:10.1002/cmdc.200900067 · Cited by 25

Identification of potential dual agonists of FXR and TGR5 using e-pharmacophore based virtual screening

Sindhu, T., & Srinivasan, P. (2015) · Molecular BioSystems · doi:10.1039/c5mb00137d · Cited by 25

Development and Application of a Virtual Screening Protocol for the Identification of Multitarget Fragments

Bottegoni, G., Veronesi, M., Bisignano, P., Kacker, P., Favia, A. D., & Cavalli, A. (2015) · ChemMedChem · doi:10.1002/cmdc.201500521 · Cited by 25

Treating mixed mania/hypomania: a review and synthesis of the evidence

Takeshima, M. (2016) · CNS Spectrums · doi:10.1017/s1092852916000845 · Cited by 25

Synergistic target combination prediction from curated signaling networks: Machine learning meets systems biology and pharmacology

Chua, H. E., Bhowmick, S. S., & Tucker‐Kellogg, L. (2017) · Methods · doi:10.1016/j.ymeth.2017.05.015 · Cited by 24

Are You Sure You Have a Good Model?

Triballeau, N., Bertrand, H., & Acher, F. (2006) · Methods and principles in medicinal chemistry · doi:10.1002/3527609164.ch15 · Cited by 23

Discovery of N-{4-[5-(4-Fluorophenyl)-3-methyl-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-acetamide (CBS-3595), a Dual p38α MAPK/PDE-4 Inhibitor with Activity against TNFα-Related Diseases

Albrecht, W., Unger, A., Bauer, S. M., & Laufer, S. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01647 · Cited by 23

Predicting targets of compounds against neurological diseases using cheminformatic methodology

Nikolic, K. M., Mavridis, L., Bautista‐Aguilera, Ó. M., Marco‐Contelles, J., Stark, H., Carreiras, M. C., Rossi, I., Massarelli, P., Agbaba, D. D., Ramsay, R. R., et al. (2014) · Journal of Computer-Aided Molecular Design · doi:10.1007/s10822-014-9816-1 · Cited by 22

Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists

Lamotte, Y., Faucher, N., Sançon, J., Pineau, O., Sautet, S., Fouchet, M.-H., Bénéton, V., Tousaint, J.-J., Saintillan, Y., Ancellin, N., et al. (2014) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2014.01.004 · Cited by 22

Identification of protein binding partners of small molecules using label-free methods

Saxena, C. (2016) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2016.1227316 · Cited by 22

Connecting Neuronal Cell Protective Pathways and Drug Combinations in a Huntington’s Disease Model through the Application of Quantitative Systems Pharmacology

Pei, F., Li, H., Henderson, M. J., Titus, S. A., Jadhav, A., Simeonov, A. M., Çobanoğlu, M. C., Mousavi, S. H., Shun, T., McDermott, L. A., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-17378-y · Cited by 21

Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism

Kashif, M., Andersson, C. R., Mansoori, S., Larsson, R. L., Nygren, P., & Gustafsson, M. G. (2017) · Oncotarget · doi:10.18632/oncotarget.21895 · Cited by 20

Turning from monogamy to strategic promiscuity

Stark, H. (2004) · Drug Discovery Today · doi:10.1016/s1359-6446(04)03208-8 · Cited by 17

Search for Histamine H3 Receptor Ligands with Combined Inhibitory Potency at HistamineN‐Methyltransferase: ω‐Piperidinoalkanamine Derivatives

Graßmann, S., Apelt, J., Ligneau, X., Pertz, H. H., Arrang, J., Ganellin, C. R., Schwartz, J.-C., Schunack, W. G., & Stark, H. (2004) · Archiv der Pharmazie · doi:10.1002/ardp.200400897 · Cited by 17

Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases

Kalash, L. N., Val, C., Azuaje, J., Loza, M. I., Svensson, F., Zoufir, A., Mervin, L., Ladds, G., Brea, J. M., Glen, R. C., et al. (2017) · Journal of Cheminformatics · doi:10.1186/s13321-017-0249-4 · Cited by 17

Selective Optimization of Side Activities (SOSA): A Promising way for Drug Discovery

Langer, T., & Wermuth, C. (2012) · Wiley eBooks · doi:10.1002/9781118098141.ch11 · Cited by 16

Applications of Multi-Target Computer-Aided Methodologies in Molecular Design of CNS Drugs

Raevsky, O. A., Mukhametov, A., Grigorev, V. Y., Ustyugov, A. A., Tsay, S., Hwu, J. R., Yarla, N. S., Tarasov, V. V., Aliev, G. M., & Бачурин, С. О. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867324666170920154111 · Cited by 16

Phenothiazinium–fluoroquinolone drug conjugates

WAINWRIGHT, M. S., Shah, A., Meegan, K., Loughran, C., Smith, A., Valli, N., & Dempster, N. M. (2010) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2009.11.022 · Cited by 15

The importance of predictive biomarkers in oncology drug development

Jørgensen, J. T. (2016) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2016.1199962 · Cited by 15

Design of Multifunctional Compounds for Cardiovascular Disease: From Natural Scaffolds to “Classical” Multitarget Approach

Bisi, A., Gobbi, S., Belluti, F., & Rampa, A. (2013) · Current Medicinal Chemistry · doi:10.2174/0929867311320130012 · Cited by 14

S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α2-Adrenoceptor Antagonist and Potential Antidepressant: I. A Mechanistic Characterization

Millan, M. J., la Cour, C. M., Chanrion, B., Dupuis, D. S., Cara, B. D., Audinot, V., Cussac, D., Newman‐Tancredi, A., Kamal, M. T., Boutin, J. A., et al. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.187468 · Cited by 14

Therapeutic Potential of Peroxisome Proliferator-Activated Receptor Modulation in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

Gellrich, L., & Merk, D. (2017) · Nuclear Receptor Research · doi:10.11131/2017/101310 · Cited by 13

MARS: Computing Three-Dimensional Alignments for Multiple Ligands Using Pairwise Similarities

Klabunde, T., Giegerich, C., & Evers, A. (2012) · Journal of Chemical Information and Modeling · doi:10.1021/ci3000369 · Cited by 12

High-throughput RNAi screen for essential genes and drug synergistic combinations in colorectal cancer

Williams, S. P., Barthorpe, A. S., Lightfoot, H. W., Garnett, M. J., & McDermott, U. (2017) · Scientific Data · doi:10.1038/sdata.2017.139 · Cited by 11

The SHROB Model of Syndrome X: Effects of Excess Dietary Sucrose

Ernsberger, P. R., Koletsky, R. J., Kline, D. D., Bedol, D., & Friedman, J. E. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb07806.x · Cited by 10

Systematic Data Mining Reveals Synergistic H3R/MCHR1 Ligands

Schaller, D., Hagenow, S., Alpert, G., Naß, A., Schulz, R., Bermúdez, M., Stark, H., & Wolber, G. (2017) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.7b00118 · Cited by 8

Dual antagonists of the bradykinin B1 and B2 receptors based on a postulated common pharmacophore from existing non-peptide antagonists

Morissette, G., Bouthillier, J., & Marceau, F. (2006) · Biological Chemistry · doi:10.1515/bc.2006.025 · Cited by 5

Pharmacophore Generation for Multiple Ligands

Handler, N. (2017) · Methods and principles in medicinal chemistry · doi:10.1002/9783527674381.ch10 · Cited by 5

The Linker Approach

Merk, D., & Schubert‐Zsilavecz, M. (2017) · Methods and principles in medicinal chemistry · doi:10.1002/9783527674381.ch8 · Cited by 5

Merged Multiple Ligands

Chen, H., Bauer, U., & Engkvist, O. (2017) · Methods and principles in medicinal chemistry · doi:10.1002/9783527674381.ch9 · Cited by 5

From serendipity to design: the evolution of drug development in oncology

Markman, M., & Peereboom, D. M. (1997) · Cleveland Clinic Journal of Medicine · doi:10.3949/ccjm.64.3.155 · Cited by 4

Charting the chemical space around the (iso)indoline scaffold, a comprehensive approach towards multitarget directed ligands

Éliás, O., Kovács, Z. Z., Wágner, G., Némethy, Z., Tarcsay, Á., & Greiner, I. (2016) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2016.07.055 · Cited by 4

Identification and Optimization of Dual PI3K/mTOR Inhibitors

Karlsson, A., & Garcı́a-Echeverrı́a, C. (2012) · Royal Society of Chemistry eBooks · doi:10.1039/9781849734912-00206 · Cited by 1

Artificial intelligence to deep learning: machine intelligence approach for drug discovery

Gupta, R., Srivastava, D., Sahu, M., Tiwari, S., Ambasta, R. K., & Kumar, P. (2021) · Molecular Diversity · doi:10.1007/s11030-021-10217-3 · Cited by 1,473

Towards the sustainable discovery and development of new antibiotics

Miethke, M., Pieroni, M., Weber, T., Brönstrup, M., Hammann, P., Halby, L., Arimondo, P. B., Glaser, P., Aigle, B., Bode, H. B., et al. (2021) · Nature Reviews Chemistry · doi:10.1038/s41570-021-00313-1 · Cited by 1,228

RNA-Based Therapeutics: From Antisense Oligonucleotides to miRNAs

Bajan, S., & Hutvágner, G. (2020) · Cells · doi:10.3390/cells9010137 · Cited by 409

Image-based profiling for drug discovery: due for a machine-learning upgrade?

Chandrasekaran, S. N., Ceulemans, H., Boyd, J. D., & Carpenter, A. E. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-00117-w · Cited by 407

Phenotypic drug discovery: recent successes, lessons learned and new directions

Vincent, F., Nueda, A., Lee, J. L. C., Schenone, M., Prunotto, M., & Mercola, M. A. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00472-w · Cited by 397

Overview of Drug Polypharmacology and Multitargeted Molecular Design

Chaudhari, R., Tan, Z., & Zhang, S. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-409547-2.12323-6 · Cited by 11

Exploring polypharmacology in the development of multi-target drugs

Sundaram, P., & Venkat, K. (2023) · International Journal of Advanced Chemistry Research · doi:10.33545/26646781.2023.v5.i2b.212

Advances in Computational Polypharmacology

Feldmann, C., & Bajorath, J. (2022) · Molecular Informatics · doi:10.1002/minf.202200190 · Cited by 14

Polypharmacology in a Single Drug: Multitarget Drugs

L. Bolognesi, M. (2013) · Current Medicinal Chemistry · doi:10.2174/0929867311320130004 · Cited by 230

Computational Multitarget Drug Design

Zhang, W., Pei, J., & Lai, L. (2017) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.6b00491 · Cited by 189