Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds
Abstract
Multitargeting compounds comprising activity on more than a single biological target have gained remarkable relevance in drug discovery owing to the complexity of multifactorial diseases such as cancer, inflammation, or the metabolic syndrome. Polypharmacological drug profiles can produce additive or synergistic effects while reducing side effects and significantly contribute to the high therapeutic success of indispensable drugs such as aspirin. While their identification has long been the result of serendipity, medicinal chemistry now tends to design polypharmacology. Modern in vitro pharmacological methods and chemical probes allow a systematic search for rational target combinations and recent innovations in computational technologies, crystallography, or fragment-based design equip multitarget compound development with valuable tools. In this Perspective, we analyze the relevance of multiple ligands in drug discovery and the versatile toolbox to design polypharmacology. We conclude that despite some characteristic challenges remaining unresolved, designed polypharmacology holds enormous potential to secure future therapeutic innovation.
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Simultaneous modulation of multiple targets by one or more chemical entities is correlated with lower doses usage.
“Additionally, the simultaneous modulation of multiple targets by one or more chemical entities is correlated to the concept of lower doses usage.8”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [8]
Cites
Takahashi, K., & Yamanaka, S. (2006) · Cell · doi:10.1016/j.cell.2006.07.024 · Cited by 26,673 · see citing works
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (1997) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(96)00423-1 · Cited by 11,484 · see citing works
Extended-Connectivity Fingerprints
Rogers, D. O. W., & Hahn, M. (2010) · Journal of Chemical Information and Modeling · doi:10.1021/ci100050t · Cited by 7,597 · see citing works
The new frontier of genome engineering with CRISPR-Cas9
Doudna, J. A., & Charpentier, E. (2014) · Science · doi:10.1126/science.1258096 · Cited by 7,062 · see citing works
Network pharmacology: the next paradigm in drug discovery
Hopkins, A. L. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.118 · Cited by 4,622 · see citing works
Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay
Molina, D. M., Jafari, R., Ignatushchenko, M., Seki, T., Larsson, E. A., Dan, C., Sreekumar, L., Cao, Y., & Nordlund, P. (2013) · Science · doi:10.1126/science.1233606 · Cited by 2,261 · see citing works
Wolber, G., & Langer, T. (2004) · Journal of Chemical Information and Modeling · doi:10.1021/ci049885e · Cited by 1,989 · see citing works
The ChEMBL bioactivity database: an update
Bento, A. P., Gaulton, A., Hersey, A., Bellis, L. J., Chambers, J. K., Davies, M., Krüger, F. A., Light, Y., Mak, L., McGlinchey, S., et al. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1031 · Cited by 1,487 · see citing works
Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework
Cook, D., Brown, D., Alexander, R., March, R., Morgan, P., Satterthwaite, G., & Pangalos, M. N. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4309 · Cited by 1,347 · see citing works
Concepts and applications of molecular similarity
Johnson, M. A., & Maggiora, G. M. (1990) · Wiley eBooks · Cited by 1,322 · see citing works
Designed Multiple Ligands. An Emerging Drug Discovery Paradigm
Morphy, R., & Ranković, Z. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm058225d · Cited by 1,237 · see citing works
Tracking cancer drugs in living cells by thermal profiling of the proteome
Savitski, M. M., Reinhard, F. B. M., Franken, H., Werner, T., Savitski, M. F., Eberhard, D., Molina, D. M., Jafari, R., Dovega, R. B., Klaeger, S., et al. (2014) · Science · doi:10.1126/science.1255784 · Cited by 1,187 · see citing works
Roth, B. L., Sheffler, D. J., & Kroeze, W. K. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1346 · Cited by 1,155 · see citing works
Multi-target-Directed Ligands To Combat Neurodegenerative Diseases
Cavalli, A., Bolognesi, M. L., Minarini, A., Rosini, M., Tumiatti, V., Recanatini, M., & Melchiorre, C. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm7009364 · Cited by 1,152 · see citing works
Polypharmacology: Challenges and Opportunities in Drug Discovery: Miniperspective
Anighoro, A., Bajorath, J., & Rastelli, G. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm5006463 · Cited by 1,131 · see citing works
Target identification using drug affinity responsive target stability (DARTS)
Lomenick, B., Hao, R., Jonai, N., Chin, R., Aghajan, M., Warburton, S., Wang, J., Wu, R. P., Gómez, F., Loo, J. A., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910040106 · Cited by 1,113 · see citing works
Multi-target therapeutics: when the whole is greater than the sum of the parts
Zimmermann, G. R., Lehár, J., & Keith, C. T. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2006.11.008 · Cited by 1,105 · see citing works
Benson, S. C., Pershadsingh, H. A., Ho, C. I., Chittiboyina, A. G., Desai, P. V., Pravenec, M., Qi, N., Wang, J., Avery, M. A., & Kurtz, T. W. (2004) · Hypertension · doi:10.1161/01.hyp.0000123072.34629.57 · Cited by 1,076 · see citing works
Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors
Bantscheff, M., Eberhard, D., Abraham, Y., Bastuck, S., Böesche, M., Hobson, S., Mathieson, T., Perrin, J., Raida, M., Rau, C., et al. (2007) · Nature Biotechnology · doi:10.1038/nbt1328 · Cited by 1,036 · see citing works
Pharmacophore modeling and applications in drug discovery: challenges and recent advances
Yang, S. (2010) · Drug Discovery Today · doi:10.1016/j.drudis.2010.03.013 · Cited by 902 · see citing works
Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery
Hann, M. M., Leach, A. R., & Harper, G. (2001) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci000403i · Cited by 882 · see citing works
The promise and peril of chemical probes
Arrowsmith, C. H., Audia, J. E., Austin, C., Baell, J., Bennett, J., Blagg, J., Bountra, C., Brennan, P. E., Brown, P. J., Bunnage, M. E., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1867 · Cited by 839 · see citing works
Automated design of ligands to polypharmacological profiles
Besnard, J., Ruda, G. F., Setola, V., Abecassis, K., Rodriguiz, R. M., Huang, X.-P., Norval, S., Sassano, M. F., Shin, A. I., Webster, L. A., et al. (2012) · Nature · doi:10.1038/nature11691 · Cited by 832 · see citing works
Do Structurally Similar Molecules Have Similar Biological Activity?
Martin, Y. C., Kofron, J. L., & Traphagen, L. M. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm020155c · Cited by 806 · see citing works
Antibody-drug conjugates: recent advances in conjugation and linker chemistries
Tsuchikama, K., & An, Z. (2016) · Protein & Cell · doi:10.1007/s13238-016-0323-0 · Cited by 792 · see citing works
From magic bullets to designed multiple ligands
Morphy, R., Kay, C., & Ranković, Z. (2004) · Drug Discovery Today · doi:10.1016/s1359-6446(04)03163-0 · Cited by 731 · see citing works
A perspective on multi‐target drug discovery and design for complex diseases
Ramsay, R. R., Popović-Nikolić, M. R., Nikolic, K. M., Uliassi, E., & Bolognesi, M. L. (2018) · Clinical and Translational Medicine · doi:10.1186/s40169-017-0181-2 · Cited by 722 · see citing works
Sirtori, C. R. (2014) · Pharmacological Research · doi:10.1016/j.phrs.2014.03.002 · Cited by 705 · see citing works
Principles in the design of ligand-targeted cancer therapeutics and imaging agents
Srinivasarao, M., Galliford, C. V., & Low, P. S. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4519 · Cited by 676 · see citing works
Wang, Y., Bryant, S. H., Cheng, T., Wang, J., Gindulytė, A., Shoemaker, B. A., Thiessen, P. A., He, S., & Zhang, J. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw1118 · Cited by 675 · see citing works
Targeting the cancer kinome through polypharmacology
Knight, Z. A., Lin, H., & Shokat, K. M. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2787 · Cited by 674 · see citing works
Franken, H., Mathieson, T., Childs, D., Sweetman, G. M. A., Werner, T., Tögel, I., Doce, C., Gade, S., Bantscheff, M., Drewes, G., et al. (2015) · Nature Protocols · doi:10.1038/nprot.2015.101 · Cited by 663 · see citing works
DeepSynergy: predicting anti-cancer drug synergy with Deep Learning
Preuer, K., Lewis, R. P. I., Hochreiter, S., Bender, A., Bulusu, K. C., & Klambauer, G. (2017) · Bioinformatics · doi:10.1093/bioinformatics/btx806 · Cited by 651 · see citing works
Dubowchik, G. M., Firestone, R. A., Padilla, L., Willner, D., Hofstead, S. J., Mosure, K. W., Knipe, J. O., Lasch, S. J., & Trail, P. A. (2002) · Bioconjugate Chemistry · doi:10.1021/bc025536j · Cited by 560 · see citing works
High-throughput crystallography for lead discovery in drug design
Blundell, T. L., Jhoti, H., & Abell, C. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd706 · Cited by 529 · see citing works
Shifting from the single to the multitarget paradigm in drug discovery
Medina‐Franco, J. L., Giulianotti, M. A., Welmaker, G. S., & Houghten, R. A. (2013) · Drug Discovery Today · doi:10.1016/j.drudis.2013.01.008 · Cited by 486 · see citing works
Polypharmacology – Foe or Friend?
Peters, J. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400856t · Cited by 477 · see citing works
Can we rationally design promiscuous drugs?
HOPKINS, A., MASON, J., & OVERINGTON, J. (2006) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2006.01.013 · Cited by 469 · see citing works
Target Identification for Small Bioactive Molecules: Finding the Needle in the Haystack
Ziegler, S., Pries, V., Hedberg, C., & Waldmann, H. (2013) · Angewandte Chemie International Edition · doi:10.1002/anie.201208749 · Cited by 466 · see citing works
Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases
Apsel, B., Blair, J. A., González, B., Nazif, T. M., Feldman, M. E., Aizenstein, B., Hoffman, R., Williams, R. L., Shokat, K. M., & Knight, Z. A. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.117 · Cited by 452 · see citing works
Talevi, A. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00205 · Cited by 397 · see citing works
Prospects for new antibiotics: a molecule-centered perspective
Walsh, C. T., & Wencewicz, T. A. (2013) · The Journal of Antibiotics · doi:10.1038/ja.2013.49 · Cited by 373 · see citing works
<i>De Novo</i> Design of Bioactive Small Molecules by Artificial Intelligence
Merk, D., Friedrich, L., Grisoni, F., & Schneider, G. (2018) · Molecular Informatics · doi:10.1002/minf.201700153 · Cited by 373 · see citing works
Self-citationNatural compounds and combination therapy in colorectal cancer treatment
Rejhova, A., Opattová, A., Čumová, A., Slíva, D., & Vodička, P. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.12.039 · Cited by 367 · see citing works
Dual kinase-bromodomain inhibitors for rationally designed polypharmacology
Ciceri, P., Müller, S., O’Mahony, A., Fedorov, O., Filippakopoulos, P., Hunt, J. P., Lasater, E. A., Pallares, G., Picaud, S., Wells, C. D., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1471 · Cited by 345 · see citing works
Chemical genetic discovery of targets and anti-targets for cancer polypharmacology
Dar, A. C., Das, T. K., Shokat, K. M., & Cagan, R. L. (2012) · Nature · doi:10.1038/nature11127 · Cited by 334 · see citing works
Dual or multi-targeting inhibitors: The next generation anticancer agents
Raghavendra, N. M., Pingili, D., Kadasi, S., Mettu, A., & Prasad, S. V. U. M. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.10.021 · Cited by 333 · see citing works
Drug repositioning and repurposing: terminology and definitions in literature
Langedijk, J., Mantel-Teeuwisse, A. K., Slijkerman, D. S., & Schutjens, M.-H. D. B. (2015) · Drug Discovery Today · doi:10.1016/j.drudis.2015.05.001 · Cited by 327 · see citing works
Designing Smart Polymer Conjugates for Controlled Release of Payloads
Seidi, F., Jenjob, R., & Crespy, D. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00006 · Cited by 320 · see citing works
Molecule-pharmacophore superpositioning and pattern matching in computational drug design
Wolber, G., Seidel, T., Bendix, F., & Langer, T. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2007.09.007 · Cited by 315 · see citing works
Multi-targeting by monotherapeutic antibacterials
Silver, L. L. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2202 · Cited by 312 · see citing works
Thermal proteome profiling monitors ligand interactions with cellular membrane proteins
Reinhard, F. B. M., Eberhard, D., Werner, T., Franken, H., Childs, D., Doce, C., Savitski, M. F., Huber, W. K., Bantscheff, M., Savitski, M. M., et al. (2015) · Nature Methods · doi:10.1038/nmeth.3652 · Cited by 310 · see citing works
In silico repositioning of approved drugs for rare and neglected diseases
Ekins, S., Williams, A. J., Krasowski, M. D., & Freundlich, J. S. (2011) · Drug Discovery Today · doi:10.1016/j.drudis.2011.02.016 · Cited by 288 · see citing works
Koutsoukas, A., Simms, B., Kirchmair, J., Bond, P. J., Whitmore, A. V., Zimmer, S., Young, M. P., Jenkins, J. L., Glick, M., Glen, R. C., et al. (2011) · Journal of Proteomics · doi:10.1016/j.jprot.2011.05.011 · Cited by 287 · see citing works
NLLSS: Predicting Synergistic Drug Combinations Based on Semi-supervised Learning
Chen, X., Ren, B., Chen, M., Wang, Q., Zhang, L., & Yan, G. (2016) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004975 · Cited by 281 · see citing works
A history of antipsychotic drug development
Shen, W. W. (1999) · Comprehensive Psychiatry · doi:10.1016/s0010-440x(99)90082-2 · Cited by 279 · see citing works
Designing multi-targeted agents: An emerging anticancer drug discovery paradigm
Fu, R.-G., Sun, Y., Sheng, W., & Liao, D. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.05.016 · Cited by 264 · see citing works
Designing Multiple Ligands – Medicinal Chemistry Strategies and Challenges
Morphy, R., & Ranković, Z. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209787315594 · Cited by 262 · see citing works
Multi-Target Drugs: The Trend of Drug Research and Development
Lu, J., Pan, W., Yuanjia, H., & Wang, Y. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040262 · Cited by 259 · see citing works
Cancer biomarkers: selecting the right drug for the right patient
Kelloff, G. J., & Sigman, C. C. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3651 · Cited by 253 · see citing works
DOGS: Reaction-Driven de novo Design of Bioactive Compounds
Hartenfeller, M., Zettl, H., Walter, M., Rupp, M., Reisen, F., Proschak, E., Weggen, S., Stark, H., & Schneider, G. (2012) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002380 · Cited by 251 · see citing works
Self-citationPoornima, P., Kumar, J. D., Zhao, Q., Blunder, M., & Efferth, T. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.06.018 · Cited by 250 · see citing works
Sideromycins: tools and antibiotics
Braun, V., Pramanik, A., Gwinner, T., Köberle, M., & Bohn, E. (2009) · BioMetals · doi:10.1007/s10534-008-9199-7 · Cited by 237 · see citing works
Krause, M., Zhu, Y., Huhn, M., Schneider‐Thoma, J., Bighelli, I., Nikolakopoulou, A., & Leucht, S. (2018) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-018-0869-3 · Cited by 234 · see citing works
Methods for High-throughput Drug Combination Screening and Synergy Scoring
He, L., Kulesskiy, E., Saarela, J., Turunen, L., Wennerberg, K., Aittokallio, T., & Tang, J. (2018) · Methods in Molecular Biology · doi:10.1007/978-1-4939-7493-1_17 · Cited by 232 · see citing works
In silico methods to address polypharmacology: current status, applications and future perspectives
Lavecchia, A., & Cerchia, C. (2015) · Drug Discovery Today · doi:10.1016/j.drudis.2015.12.007 · Cited by 228 · see citing works
Multifunctional compounds: Smart molecules for multifactorial diseases
Bansal, Y., & Silakari, O. (2014) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2014.01.060 · Cited by 215 · see citing works
Comparative Assessment of Scoring Functions on an Updated Benchmark: 1. Compilation of the Test Set
Li, Y., Liu, Z., Li, J., Han, L., Liu, J., Zhao, Z., & Wang, R. (2014) · Journal of Chemical Information and Modeling · doi:10.1021/ci500080q · Cited by 214 · see citing works
Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms
Kleinstreuer, N. C., Yang, J., Berg, E. L., Knudsen, T. B., Richard, A. M., Martin, M. T., Reif, D. M., Judson, R. S., Polokoff, M., Dix, D. J., et al. (2014) · Nature Biotechnology · doi:10.1038/nbt.2914 · Cited by 211 · see citing works
Fragments, network biology and designing multiple ligands
Morphy, R., & Ranković, Z. (2006) · Drug Discovery Today · doi:10.1016/j.drudis.2006.12.006 · Cited by 204 · see citing works
Selective Optimization of Side Activities: Another Way for Drug Discovery
Wermuth, C. G. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm030480f · Cited by 202 · see citing works
The Physicochemical Challenges of Designing Multiple Ligands
Morphy, R., & Ranković, Z. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm0603015 · Cited by 194 · see citing works
Metabolic effect of telmisartan and losartan in hypertensive patients with metabolic syndrome
Vitale, C., Mercuro, G. G., Castiglioni, C., Cornoldi, A., Tulli, A., Fini, M., Volterrani, M., & Rosano, G. M. C. (2005) · Cardiovascular Diabetology · doi:10.1186/1475-2840-4-6 · Cited by 193 · see citing works
Modern Phenotypic Drug Discovery Is a Viable, Neoclassic Pharma Strategy
Lee, J. A., Uhlik, M. T., Moxham, C. M., Tomandl, D., & Sall, D. J. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm201649s · Cited by 190 · see citing works
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 186 · see citing works
Development and Properties of β-Glucuronide Linkers for Monoclonal Antibody−Drug Conjugates
Jeffrey, S. C., Andreyka, J. B., Bernhardt, S. X., Kissler, K. M., Kline, T. B., Lenox, J. S., Moser, R. F., Nguyen, M. T., Okeley, N. M., Stone, I. J., et al. (2006) · Bioconjugate Chemistry · doi:10.1021/bc0600214 · Cited by 183 · see citing works
Modeling Parkinson's Disease in Primates: The MPTP ModelPreprint
Porras, G., Li, Q., & Bézard, E. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009308 · Cited by 180 · see citing works
Pharmacophore-Based Virtual Screening
Sun, H. (2008) · Current Medicinal Chemistry · doi:10.2174/092986708784049630 · Cited by 176 · see citing works
Dias, K. S. T., & Viegas, C. (2014) · Current Neuropharmacology · doi:10.2174/1570159x1203140511153200 · Cited by 174 · see citing works
Da, C., & Kireev, D. (2014) · Journal of Chemical Information and Modeling · doi:10.1021/ci500319f · Cited by 172 · see citing works
De Novo Design at the Edge of Chaos
Schneider, P., & Schneider, G. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01849 · Cited by 167 · see citing works
Reutlinger, M., Koch, C. P., Reker, D., et al. (2013) · Molecular Informatics · doi:10.1002/minf.201200141 · Cited by 166 · see citing works
How to design multi-target drugs
Korcsmaros, T. D., Szalay, M., Böde, C., Kovács, I. A., & Csermely, P. (2007) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2.6.799 · Cited by 162 · see citing works
Hartenfeller, M., & Schneider, G. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-839-3_12 · Cited by 160 · see citing works
Liu, R., Miller, P. A., Vakulenko, S. B., Stewart, N. K., Boggess, B., & Miller, M. J. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00218 · Cited by 153 · see citing works
Multi-Target Directed Donepezil-Like Ligands for Alzheimer's Disease
Unzeta, M., Esteban, G., Bolea, I., Fogel, W. A., Ramsay, R. R., Youdim, M. B. H., Tipton, K. F., & Marco, J. L. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00205 · Cited by 151 · see citing works
Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent
Artis, D. R., Lin, J. J., Zhang, C., Wang, W., Mehra, U., Perreault, M., Erbe, D. V., Krupka, H. I., England, B. P., Arnold, J., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811325106 · Cited by 150 · see citing works
Hybrid Compounds as Direct Multitarget Ligands: A Review
Pedrosa, M. O., da Cruz, R. M. D., Viana, J. D. O., et al. (2016) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026616666160927160620 · Cited by 150 · see citing works
Epigenetic polypharmacology: from combination therapy to multitargeted drugs
de Lera, Á. R., & Ganesan, A. (2016) · Clinical Epigenetics · doi:10.1186/s13148-016-0271-9 · Cited by 148 · see citing works
Wang, L., Esteban, G., Ojima, M., Bautista‐Aguilera, Ó. M., Inokuchi, T., Moraleda, I., Iriepa, I., Samadi, A., Youdim, M. B. H., Romero, A., et al. (2014) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2014.04.078 · Cited by 143 · see citing works
Wei, D., Jiang, X., Zhou, L., Chen, J., Chen, Z., He, C., Yang, K., Liu, Y., Pei, J., & Lai, L. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm8010096 · Cited by 141 · see citing works
Dalli, J., & Serhan, C. N. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14336 · Cited by 138 · see citing works
Inhibitors of the Arachidonic Acid Cascade: Interfering with Multiple Pathways
Meirer, K., Steinhilber, D., & Proschak, E. (2013) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.12134 · Cited by 137 · see citing works
Self-citationLiver-specific drug targeting by coupling to bile acids.
Kramer, W., Wess, G., Schubert, G., et al. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)37003-6 · Cited by 134 · see citing works
Ghosh, M., Miller, P. A., Möllmann, U., Claypool, W. D., Schroeder, V. A., Wolter, W. R., Suckow, M. A., Yu, H., Li, S., Huang, W., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00102 · Cited by 134 · see citing works
Wencewicz, T. A., Long, T. E., Möllmann, U., & Miller, M. J. (2013) · Bioconjugate Chemistry · doi:10.1021/bc300610f · Cited by 132 · see citing works
Wencewicz, T. A., & Miller, M. J. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400265k · Cited by 128 · see citing works
Li, X., Xu, Y., Cui, H. S., Huang, T., Wang, D., Lian, B., Li, W., Qin, G., Chen, L., & Xie, L. (2017) · Artificial Intelligence in Medicine · doi:10.1016/j.artmed.2017.05.008 · Cited by 127 · see citing works
Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity
Tuplin, E. W. N., & Holahan, M. R. (2017) · Current Neuropharmacology · doi:10.2174/1570159x15666170413115754 · Cited by 124 · see citing works
Dynamic tuneable G protein-coupled receptor monomer-dimer populations
Dijkman, P. M., Castell, O. K., Goddard, A. D., Muñoz-García, J. C., de Graaf, C., Wallace, M. I., & Watts, A. G. (2018) · Nature Communications · doi:10.1038/s41467-018-03727-6 · Cited by 121 · see citing works
Harnessing synthetic lethality to predict the response to cancer treatment
Lee, J. S., Das, A., Jerby‐Arnon, L., Arafeh, R., Auslander, N., Davidson, M. A., McGarry, L., James, D. T., Amzallag, A., Park, S. G., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04647-1 · Cited by 120 · see citing works
Bolognesi, M. L., Cavalli, A., & Melchiorre, C. (2008) · Neurotherapeutics · doi:10.1016/j.nurt.2008.10.042 · Cited by 117 · see citing works
Comparative Analysis of Pharmacophore Screening Tools
Sanders, M. P. A., Barbosa, A. J. M., Zarzycka, B. A., Nicolaes, G. A. F., Klomp, J. P. G., de Vlieg, J., & Río, A. D. (2012) · Journal of Chemical Information and Modeling · doi:10.1021/ci2005274 · Cited by 117 · see citing works
The role of fragment-based and computational methods in polypharmacology
Bottegoni, G., Favia, A. D., Recanatini, M., & Cavalli, A. (2011) · Drug Discovery Today · doi:10.1016/j.drudis.2011.08.002 · Cited by 116 · see citing works
Dynamic Simulations on the Arachidonic Acid Metabolic Network
Yang, K., Ma, W., Liang, H., Ouyang, Q., Tang, C., & Lai, L. (2007) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0030055 · Cited by 115 · see citing works
Naidu, P. S., Booker, L., Cravatt, B. F., & Lichtman, A. H. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.143487 · Cited by 114 · see citing works
Strategies for modern biomarker and drug development in oncology
Smith, A. D., Roda, D., & Yap, T. A. (2014) · Journal of Hematology & Oncology · doi:10.1186/s13045-014-0070-8 · Cited by 111 · see citing works
Hitting multiple targets with multimeric ligands
Handl, H. L., Vágner, J., Han, H., Mash, E. A., Hruby, V. J., & Gillies, R. J. (2004) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.8.6.565 · Cited by 111 · see citing works
Prati, F., Cavalli, A., & Bolognesi, M. (2016) · Molecules · doi:10.3390/molecules21040466 · Cited by 110 · see citing works
Kurtz, S. E., Eide, C. A., Kaempf, A. J., Khanna, V., Savage, S. L., Rofelty, A., English, I. A., Ho, H., Pandya, R., Bolosky, W. J., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1703094114 · Cited by 109 · see citing works
Drug discovery and development for rare genetic disorders
Sun, W., Zheng, W., & Simeonov, A. (2017) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.38326 · Cited by 107 · see citing works
Veillard, N. R., & Mach, F. (2002) · Cellular and Molecular Life Sciences · doi:10.1007/pl00012505 · Cited by 106 · see citing works
Barillari, C., Marcou, G., & Rognan, D. (2008) · Journal of Chemical Information and Modeling · doi:10.1021/ci800064z · Cited by 106 · see citing works
Bautista‐Aguilera, Ó. M., Hagenow, S., Palomino‐Antolin, A., Farré‐Alins, V., Ismaili, L., Joffrin, P., Jimeno, M. L., Soukup, O., Janočková, J., Kalinowsky, L., et al. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201706072 · Cited by 105 · see citing works
Self-citationProfiling Bioactivity of the ToxCast Chemical Library Using BioMAP Primary Human Cell Systems
Houck, K., Dix, D., Judson, R., Kavlock, R., Yang, J., & Berg, E. (2009) · Journal of biomolecular screening · doi:10.1177/1087057109345525 · Cited by 101 · see citing works
Tschinke, V., & Cohen, N. C. (1993) · Journal of Medicinal Chemistry · doi:10.1021/jm00076a016 · Cited by 97 · see citing works
A Computational Approach for Identifying Synergistic Drug Combinations
Gayvert, K. M., Aly, O., Platt, J. T., Bosenberg, M., Stern, D. F., & Elemento, O. (2017) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005308 · Cited by 97 · see citing works
Polypharmacology in Precision Oncology: Current Applications and Future Prospects
Antolín, A. A., Workman, P., Mestres, J., & Al‐Lazikani, B. (2016) · Current Pharmaceutical Design · doi:10.2174/1381612822666160923115828 · Cited by 96 · see citing works
High-Throughput Crystallography: Reliable and Efficient Identification of Fragment Hits
Schiebel, J., Krimmer, S. G., Röwer, K., et al. (2016) · Structure · doi:10.1016/j.str.2016.06.010 · Cited by 94 · see citing works
Fronik, P., Gaiser, B. I., & Pedersen, D. S. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01601 · Cited by 94 · see citing works
Improving the efficacy-safety balance of polypharmacology in multi-target drug discovery
Ravikumar, B., & Aittokallio, T. A. (2017) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2018.1413089 · Cited by 93 · see citing works
Rationally Designed Multi-Targeted Agents Against Neurodegenerative Diseases
Geldenhuys, W. J., & der Schyf, C. J. V. (2013) · Current Medicinal Chemistry · doi:10.2174/09298673113209990112 · Cited by 92 · see citing works
One for All? Hitting Multiple Alzheimer's Disease Targets with One Drug
Hughes, R. E., Nikolic, K. M., & Ramsay, R. R. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00177 · Cited by 92 · see citing works
Orthosteric/Allosteric Bitopic Ligands: Going Hybrid at GPCRs
Valant, C., Sexton, P. M., & Christopoulos, A. (2009) · Molecular Interventions · doi:10.1124/mi.9.3.6 · Cited by 91 · see citing works
Kinase-likeness and Kinase-Privileged Fragments: Toward Virtual Polypharmacology
Aronov, A. M., McClain, B., Moody, C. S., & Murcko, M. A. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm701021b · Cited by 91 · see citing works
Multitarget drugs: the present and the future of cancer therapy
Petrelli, A., & Valabrega, G. (2009) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656560902781907 · Cited by 90 · see citing works
3-Benzisothiazolylpiperazine Derivatives as Potential Atypical Antipsychotic Agents
Howard, H. R., Lowe, J. A., III, Seeger, T., et al. (1996) · Journal of Medicinal Chemistry · doi:10.1021/jm950625l · Cited by 90 · see citing works
5-HT1 and 5-HT2: binding characteristics of some quipazine analogs
Glennon, R. A., Slusher, R. M., Lyon, R. A., et al. (1986) · Journal of Medicinal Chemistry · doi:10.1021/jm00161a038 · Cited by 89 · see citing works
Opportunities and Challenges for Fatty Acid Mimetics in Drug Discovery
Proschak, E., Heitel, P., Kalinowsky, L., & Merk, D. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01287 · Cited by 89 · see citing works
Self-citationCefiderocol: a novel siderophore cephalosporin
Choi, J. J., & McCarthy, M. W. (2018) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2018.1426745 · Cited by 88 · see citing works
Schmidt, J., Rotter, M., Weiser, T., Wittmann, S. K., Weizel, L., Kaiser, A., Heering, J., Goebel, T., Angioni, C., Wurglics, M., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00398 · Cited by 87 · see citing works
Self-citationMiller, M. L., Molinelli, E. J., Nair, J. S., Sheikh, T., Samy, R., Jing, X., He, Q., Korkut, A., Crago, A. M., Singer, S., et al. (2013) · Science Signaling · doi:10.1126/scisignal.2004014 · Cited by 86 · see citing works
Aronson, J. K. (2004) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2004.02067.x · Cited by 85 · see citing works
Experimental Models of Parkinson's Disease: From the Static to the Dynamic
Bézard, E., Imbert, C., & Gross, C. E. (1998) · Reviews in the Neurosciences · doi:10.1515/revneuro.1998.9.2.71 · Cited by 83 · see citing works
Cardioprotection by Metformin: Beneficial Effects Beyond Glucose Reduction
Varjabedian, L., Bourji, M., Pourafkari, L., & Nader, N. D. (2018) · American Journal of Cardiovascular Drugs · doi:10.1007/s40256-018-0266-3 · Cited by 83 · see citing works
Multivalent Ligand: Design Principle for Targeted Therapeutic Delivery Approach
Chittasupho, C. (2012) · Therapeutic Delivery · doi:10.4155/tde.12.99 · Cited by 81 · see citing works
Dual Aromatase−Steroid Sulfatase Inhibitors
Woo, L. W. L., Bubert, C., Sutcliffe, O. B., Smith, A., Chander, S. K., Mahon, M. F., Purohit, A., Reed, M. J., & Potter, B. V. L. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm061462b · Cited by 80 · see citing works
Quantification of Pathway Cross-talk Reveals Novel Synergistic Drug Combinations for Breast Cancer
Jaeger, S., Igea, A., Arroyo, R., Alcalde, V., Cánovas, B., Orozco, M., Nebreda, Á. R., & Aloy, P. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-0097 · Cited by 77 · see citing works
The use of natural compounds for the targeting and chemoprevention of ovarian cancer
Pistollato, F., Iglesias, R. C., Ruíz, R., et al. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.09.050 · Cited by 76 · see citing works
Wong, E. H. F., Tarazi, F. I., & Shahid, M. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.02.001 · Cited by 75 · see citing works
Acid-cleavable thiomaleamic acid linker for homogeneous antibody–drug conjugation
Castañeda, L., Maruani, A., Schumacher, F. F., Miranda, E., Chudasama, V., Chester, K. A., Baker, J. R., Smith, M. E. B., & Caddick, S. (2013) · Chemical Communications · doi:10.1039/c3cc45220d · Cited by 75 · see citing works
Huang, L., Jiang, Y., & Chen, Y. (2017) · Scientific Reports · doi:10.1038/srep40752 · Cited by 75 · see citing works
Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration
Ramsay, R. R., Májeková, M., Medina, M., & Valoti, M. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00375 · Cited by 74 · see citing works
Drug Repurposing and the Medicinal Chemist
Aubé, J. (2012) · ACS Medicinal Chemistry Letters · doi:10.1021/ml300114c · Cited by 73 · see citing works
Zumla, A. I., Rao, M., Dodoo, E., & Maeurer, M. J. (2016) · BMC Medicine · doi:10.1186/s12916-016-0635-1 · Cited by 73 · see citing works
Target Fishing for Chemical Compounds Using Target-Ligand Activity Data and Ranking Based Methods
Wale, N., & Karypis, G. (2009) · Journal of Chemical Information and Modeling · doi:10.1021/ci9000376 · Cited by 70 · see citing works
Apelt, J., Ligneau, X., Pertz, H. H., et al. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm0110845 · Cited by 69 · see citing works
Designed Multiple Ligands: Basic Research vs Clinical Outcomes
Costantino, L., & Barlocco, D. (2012) · Current Medicinal Chemistry · doi:10.2174/092986712801215883 · Cited by 69 · see citing works
Prati, F., Simone, A. D., Armirotti, A., Summa, M., Pizzirani, D., Scarpelli, R., Bertozzi, S. M., Pérez, D. I., Andrisano, V., Pérez‐Castillo, A., et al. (2015) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5b00121 · Cited by 68 · see citing works
De Novo Design of Multitarget Ligands with an Iterative Fragment-Growing Strategy
Shang, E., Yuan, Y., Chen, X., Liu, Y., Pei, J., & Lai, L. (2014) · Journal of Chemical Information and Modeling · doi:10.1021/ci500021v · Cited by 68 · see citing works
Polypharmacology of dopamine receptor ligands
Butini, S., Nikolic, K. M., Kassel, S., Brückmann, H., Filipić, S., Agbaba, D. D., Gemma, S., Brogi, S., Brindisi, M., Campiani, G., et al. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.03.011 · Cited by 67 · see citing works
Self-citationDolles, D., Hoffmann, M., Gunesch, S., Marinelli, O., Möller, J., Santoni, G., Chatonnet, A., Lohse, M. J., Wittmann, H.-J., Strasser, A., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01760 · Cited by 67 · see citing works
Al‐Ali, H., Lee, D.-H., Danzi, M. C., Nassif, H., Gautam, P., Wennerberg, K., Zuercher, B., Drewry, D. H., Lee, J. K., Lemmon, V., et al. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00289 · Cited by 65 · see citing works
Designed Multiple Ligands: An Emerging Anti-HIV Drug Discovery Paradigm
Zhan, P., & Liu, X. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209788453266 · Cited by 64 · see citing works
Tintori, C., Corradi, V., Magnani, M., et al. (2008) · Journal of Chemical Information and Modeling · doi:10.1021/ci800105p · Cited by 64 · see citing works
Aromatase and Dual Aromatase‐Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates
Wood, P. M., Woo, L. W. L., THOMAS, M. P., Mahon, M. F., Purohit, A., & Potter, B. V. L. (2011) · ChemMedChem · doi:10.1002/cmdc.201100145 · Cited by 64 · see citing works
Multitarget ligands in antibacterial research: progress and opportunities
East, S. P., & Silver, L. L. (2012) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2013.743991 · Cited by 64 · see citing works
New Insights Into the Anti-Diabetic Actions of Metformin: From the Liver to the Gut
Wu, T., Horowitz, M., & Rayner, C. K. (2017) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2017.1273769 · Cited by 64 · see citing works
Serotonin, β‐amyloid, and cognition in Parkinson disease
Kotagal, V., Spino, C., Bohnen, N. I., Koeppe, R., & Albin, R. L. (2018) · Annals of Neurology · doi:10.1002/ana.25236 · Cited by 64 · see citing works
Wambaugh, M. A., Shakya, V. P. S., Lewis, A. J., Mulvey, M. A., & Brown, J. C. S. (2017) · PLOS Biology · doi:10.1371/journal.pbio.2001644 · Cited by 63 · see citing works
A whole-animal platform to advance a clinical kinase inhibitor into new disease space
Sonoshita, M., Scopton, A. P., Ung, P. M. U., Murray, M. A., Silber, L., Maldonado, A. Y., Real, A. M., Schlessinger, A., Cagan, R. L., & Dar, A. C. (2018) · Nature Chemical Biology · doi:10.1038/nchembio.2556 · Cited by 63 · see citing works
Imig, J. D., Walsh, K., Khan, A. H., Nagasawa, T., Shaw, M. C., Shaw, S. M., & Hammock, B. D. (2012) · Experimental Biology and Medicine · doi:10.1258/ebm.2012.012225 · Cited by 60 · see citing works
The story of antipsychotics: Past and present
Ramachandraiah, C., Subramaniam, N., & Tancer, M. E. (2009) · Indian Journal of Psychiatry · doi:10.4103/0019-5545.58304 · Cited by 60 · see citing works
Serendipity in Cancer Drug Discovery: Rational or Coincidence?
Prasad, S., Gupta, S. C., & Aggarwal, B. B. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.03.004 · Cited by 59 · see citing works
Li, Y., Wang, P., Li, X. X., Yu, C. Y., Yang, H. J., Zhou, J., Xue, W., Tan, J., & Zhu, F. (2016) · PLoS ONE · doi:10.1371/journal.pone.0165737 · Cited by 59 · see citing works
Tao, L., Zhu, F., Xu, F., Chen, Z., Jiang, Y., & Chen, Y. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.09.019 · Cited by 56 · see citing works
Small molecules with anti-inflammatory properties in clinical development
Hanke, T., Merk, D., Steinhilber, D., Geißlinger, G., & Schubert‐Zsilavecz, M. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.11.011 · Cited by 54 · see citing works
Self-citationCasimiro‐Garcia, A., Filzen, G. F., Flynn, D. A., Bigge, C. F., Chen, J., Davis, J. A., Dudley, D. A., Edmunds, J. J., Esmaeil, N., Geyer, A. G., et al. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm200409s · Cited by 53 · see citing works
1-Naphthylpiperazine derivatives as potential atypical antipsychotic agents
Lowe, J. A., III, Seeger, T., Nagel, A. A., et al. (1991) · Journal of Medicinal Chemistry · doi:10.1021/jm00110a016 · Cited by 53 · see citing works
Blöcher, R., Lamers, C., Wittmann, S. K., Merk, D., Hartmann, M., Weizel, L., Diehl, O., Brüggerhoff, A., Boß, M., Kaiser, A., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01239 · Cited by 53 · see citing works
Self-citationMulti-target therapeutics for neuropsychiatric and neurodegenerative disorders
Bawa, P., Pradeep, P., Kumar, P., Choonara, Y. E., Modi, G., & Pillay, V. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2016.08.001 · Cited by 53 · see citing works
High-content screening of small compounds on human embryonic stem cells.
Barbaric, I., Gokhale, P., & Andrews, P. (2010) · Biochemical Society Transactions · doi:10.1042/bst0381046 · Cited by 52 · see citing works
The pleiotropic functions of aspirin: mechanisms of action
Amin, A. R., Attur, M. G., Pillinger, M. H., et al. (1999) · Cellular and Molecular Life Sciences · doi:10.1007/s000180050432 · Cited by 51 · see citing works
Arooj, M., Sakkiah, S., Cao, G. P., & Lee, K. W. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060470 · Cited by 51 · see citing works
Dual-Target Virtual Screening by Pharmacophore Elucidation and Molecular Shape Filtering
Moser, D. M., Wisniewska, J. M., Hahn, S., et al. (2012) · ACS Medicinal Chemistry Letters · doi:10.1021/ml200286e · Cited by 50 · see citing works
Prediction of Antibiotic Interactions Using Descriptors Derived from Molecular Structure
Mason, D. J., Stott, I. P., Ashenden, S. K., Weinstein, Z., Karakoc, I., Meral, S., Kuru, N., Bender, A., & Cokol, M. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00204 · Cited by 50 · see citing works
Advances in computational approaches in identifying synergistic drug combinations
Sheng, Z., Sun, Y., Yin, Z., Tang, K., & Cao, Z. (2017) · Briefings in Bioinformatics · doi:10.1093/bib/bbx047 · Cited by 50 · see citing works
Effects of Aspirin on Endothelial Function and Hypertension
Dzeshka, M. S., Shantsila, A., & Lip, G. Y. H. (2016) · Current Hypertension Reports · doi:10.1007/s11906-016-0688-8 · Cited by 47 · see citing works
Ko, W. K. D., & Bézard, E. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.07.020 · Cited by 47 · see citing works
Serotonergic Approaches in Parkinson's Disease: Translational Perspectives, an Update.
Huot, P., Sgambato-Faure, V., Fox, S., & McCreary, A. (2017) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6b00440 · Cited by 46 · see citing works
Synthesis of bile acid - drug conjugates: Potential drug - shuttles for liver specific targeting
Wess, G., Kramer, W., Schubert, G., et al. (1993) · Tetrahedron Letters · doi:10.1016/0040-4039(93)89021-h · Cited by 45 · see citing works
Accessing target information by virtual parallel screening—The impact on natural product research
Rollinger, J. M. (2008) · Phytochemistry Letters · doi:10.1016/j.phytol.2008.12.002 · Cited by 45 · see citing works
Frett, B., Carlomagno, F., Moccia, M. L., Brescia, A., Federico, G., Falco, V. D., Admire, B., Chen, Z., Qi, W., Santoro, M. M., et al. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201501104 · Cited by 45 · see citing works
Lin, H.-H., Zhang, L., Yan, R., Lu, J., & Yuanjia, H. (2017) · Scientific Reports · doi:10.1038/s41598-017-12061-8 · Cited by 45 · see citing works
ADME and Safety Aspects of Non-cleavable Linkers in Drug Discovery and Development
Walles, M., Connor, A., & Hainzl, D. (2018) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026618666180118153502 · Cited by 45 · see citing works
The Chemical Design and Synthesis of Linkers Used in Antibody Drug Conjugates
Frigerio, M., & Kyle, A. F. (2018) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026618666180118155847 · Cited by 44 · see citing works
Khan, A. H., Kolb, L. L., Skibba, M. E., Hartmann, M., Blöcher, R., Proschak, E., & Imig, J. D. (2018) · Diabetologia · doi:10.1007/s00125-018-4685-0 · Cited by 44 · see citing works
Self-citationHe, C., Wu, Y., Lai, Y., Cai, Z., Liu, Y., & Lai, L. (2012) · Molecular BioSystems · doi:10.1039/c2mb05503a · Cited by 43 · see citing works
Characterization of New PPARγ Agonists: Analysis of Telmisartan’s Structural Components
Goebel, M., Clemenz, M., Staels, B., et al. (2009) · ChemMedChem · doi:10.1002/cmdc.200800285 · Cited by 43 · see citing works
Hu, H., Zhao, X., Kaushik, S., Robillard, L., Barthelet, A., Lin, K., Shah, K. N., Simmons, A. D., Raponi, M., Harding, T. C., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.093 · Cited by 42 · see citing works
Jasper, J., Humbeck, L., Brinkjost, T., & Koch, O. (2018) · Journal of Cheminformatics · doi:10.1186/s13321-018-0264-0 · Cited by 42 · see citing works
Use of biomarkers in ALS drug development and clinical trials
Bakkar, N., Boehringer, A. V., & Bowser, R. P. (2014) · Brain Research · doi:10.1016/j.brainres.2014.10.031 · Cited by 41 · see citing works
Leveraging Large-scale Behavioral Profiling in Zebrafish to Explore Neuroactive Polypharmacology
McCarroll, M. N., Gendelev, L., Keiser, M. J., & Kokel, D. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.5b00800 · Cited by 41 · see citing works
Khan, N., Saad, A. K., Nurulain, S. M., Darras, F. H., Decker, M. W., & Sadek, B. S. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.10.022 · Cited by 40 · see citing works
Targeting Epigenetic Networks with Polypharmacology: A New Avenue to Tackle Cancer
Franci, G., Miceli, M., & Altucci, L. (2010) · Epigenomics · doi:10.2217/epi.10.62 · Cited by 39 · see citing works
Telmisartan Improves Insulin Resistance: A Meta-Analysis
Wang, Y., Qiao, S., De-wu, H., et al. (2018) · American Journal of Therapeutics · doi:10.1097/mjt.0000000000000733 · Cited by 39 · see citing works
Exploring the Chemical Space of Multitarget Ligands Using Aligned Self-Organizing Maps
Achenbach, J., Klingler, F., Blöcher, R., et al. (2013) · ACS Medicinal Chemistry Letters · doi:10.1021/ml4002562 · Cited by 38 · see citing works
Hybrid Dual Aromatase-Steroid Sulfatase Inhibitors with Exquisite Picomolar Inhibitory Activity
Woo, L. W. L., Bubert, C., Purohit, A., et al. (2010) · ACS Medicinal Chemistry Letters · doi:10.1021/ml100273k · Cited by 38 · see citing works
Liu, Y., & Zhao, H. (2016) · Bioinformatics · doi:10.1093/bioinformatics/btw509 · Cited by 38 · see citing works
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 · see citing works
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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 · see citing works
“It is best suited for designing a promising therapeutic agent for more complex diseases such as cancer, neurodegenerative disease (NDDs), diabetes, heart failure, and many others [353–355].”
BackgroundA Perspective on Multi-target Drugs for Alzheimer’s Disease
Benek, O., Korabecny, J., & Soukup, O. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.04.008 · Cited by 260 · see citing works
Albertini, C., Salerno, A., de Sena Murteira Pinheiro, P., & Bolognesi, M. L. (2021) · Medicinal Research Reviews · doi:10.1002/med.21699 · Cited by 179 · see citing works
De Simone, A., Tumiatti, V., Andrisano, V., & Milelli, A. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00931 · Cited by 110 · see citing works
Enhancing autophagy in Alzheimer's disease through drug repositioning
Eshraghi, M., Ahmadi, M., Afshar, S., Lorzadeh, S., Adlimoghaddam, A., Rezvani Jalal, N., West, R., Dastghaib, S., Igder, S., Torshizi, S. R. N., et al. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108171 · Cited by 89 · see citing works
Development of Dual Inhibitors Targeting Epidermal Growth Factor Receptor in Cancer Therapy
Tan, L., Zhang, J., Wang, Y., Wang, X., Wang, Y., Zhang, Z., Shuai, W., Wang, G., Chen, J., Wang, C., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01714 · Cited by 88 · see citing works
Douglass, E. F., Allaway, R. J., Szalai, B., Wang, W., Tian, T., Fernández-Torras, A., Realubit, R., Karan, C., Zheng, S., Pessia, A., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2021.100492 · Cited by 68 · see citing works
He, F., Chou, C. J., Scheiner, M., Poeta, E., Yuan Chen, N., Gunesch, S., Hoffmann, M., Sotriffer, C., Monti, B., Maurice, T., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01940 · Cited by 66 · see citing works
Scheiner, M., Dolles, D., Gunesch, S., Hoffmann, M., Nabissi, M., Marinelli, O., Naldi, M., Bartolini, M., Petralla, S., Poeta, E., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00623 · Cited by 49 · see citing works
Jiang, X., Zhou, J., Wang, Y., Chen, L., Duan, Y., Huang, J., Liu, C., Chen, Y., Liu, W., Sun, H., et al. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112751 · Cited by 39 · see citing works
Multitarget PPARγ Agonists as Innovative Modulators of the Metabolic Syndrome
Ammazzalorso, A., Maccallini, C., Amoia, P., & Amoroso, R. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.04.030 · Cited by 39 · see citing works
Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer’s Disease: From In Silico to In Vivo
Stern, N., Gacs, A., Tátrai, E., Flachner, B., Hajdú, I., Dobi, K., Bágyi, I., Dormán, G., Lőrincz, Z., Cseh, S., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113098 · Cited by 35 · see citing works
Design and structural optimization of dual FXR/PPARδ activators
Schierle, S., Neumann, S., Heitel, P., Willems, S., Kaiser, A., Pollinger, J., & Merk, D. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00618 · Cited by 34 · see citing works
Self-citationDevelopment of new Alzheimer’s disease drug candidates using donepezil as a key model
Eissa, K. I., Kamel, M. M., Mohamed, L. W., & Kassab, A. E. (2023) · Archiv der Pharmazie · doi:10.1002/ardp.202200398 · Cited by 20 · see citing works
- Authors
- Proschak, E., Stark, H., & Merk, D.
- Affiliations
- Goethe University Frankfurt (DE)
- Heinrich Heine University Düsseldorf (DE)
- Corresponding author
- Merk, Daniel
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-07-23
- Volume
- 62
- Issue
- 2
- Pages
- 420-444
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2884740260
- Cited by
- 498
- References
- 251
- Citations by year
- 2026: 51 · 2025: 56 · 2024: 74 · 2023: 60 · 2022: 86 · 2021: 64 · 2020: 67 · 2019: 39 · 2018: 1
- FWCI
- 35.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Publikationsdatenbank der Fraunhofer-Gesellschaft (Fraunhofer-Gesellschaft) (submittedVersion)
- Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
- Funders
- Eidgen?ssische Technische Hochschule Z?rich (16-2 FEL-07)
- Deutsche Forschungsgemeinschaft (SFB1039, PR1405/2-2, PR1405/4-1)
- European Cooperation in Science and Technology (CA15135)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- polypharmacology, multi-target drug design, drug discovery, chemical probes, fragment-based design, crystallography, computer-aided drug design, complex diseases, drug synergy, side effect reduction
- MeSH terms
- Machine Learning, Animals, Chemistry, Pharmaceutical, Humans, Ligands, Structure-Activity Relationship, Drug Design, Crystallography, X-Ray, Models, Animal, Metabolic Networks and Pathways
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