Abstract
‘Drug promiscuity’ refers to a drug that can act on multiple molecular targets, exhibiting similar or different pharmacological effects. Drugs may interact with unwanted targets, leading to off-target effects (one of the main reasons for side effects). Thus, intervention to prevent off-target effects in the early stages of drug discovery could reduce the risk of failure. The conversion between target and off-target effects is important for drug repurposing. Drug repurposing strategies could reduce research and development costs. This review details the research progress in the rational application of drug promiscuity for the discovery of multi-target drugs, drug repurposing and improving druggability in medicinal chemistry over the last 5 years.
Graphical abstract
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Target-based drug discovery: is something wrong? Drug Discov. Today 10(2), 139–147 (2005).
- 2 . Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects. BMC Pharmacol. Toxicol. 18, 18 (2017).
- 3 . Drug promiscuity. Acta Pharm. Sin. 46(4), 361–369 (2011).
- 4 3-benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents. J. Med. Chem. 39(1), 143–148 (1996).
- 5 . High-resolution view of compound promiscuity [version 2; referees: 3 approved]. F1000Res. 2, 144 (2013).
- 6 . Determing the degree of promiscuity of extensively assayed compounds. PLoS ONE 11(4), e0153873 (2016).
- 7 . Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. J. Cardiovasc. Electr. 10(6), 836–843 (1999).
- 8 . Trends in development and approval times for new therapeutics in the United States. Nat. Rev. Drug Discov. 2(9), 695–702 (2003).
- 9 . Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 3(8), 673–683 (2004).
- 10 . Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat. Rev. Drug Discov. 5(8), 689–702 (2006).
- 11 . Is there a case for selectively promiscuous anticancer drugs? Drug Discov. Today 14(1), 1–5 (2009).
- 12 Potential strategies for increasing drug-discovery productivity. Future Med. Chem. 6(5), 515–527 (2014).
- 13 . Can we rationally design promiscuous drugs? Curr. Opin. Struc. Biol. 16(1), 127–136 (2006).
- 14 . Contributions of molecular properties to drug promiscuity. J. Med. Chem. 56(5), 1789–1795 (2013). •• An excellent review mainly focused on the contribution of molecular properties to drug promiscuity.
- 15 . Polypharmacology: challenges and opportunities in drug discovery. J. Med. Chem. 57(19), 7874–7887 (2014). • This perspective mainly introduces advantages and disadvantages of multi-target versus combination therapies, discussion of potential drug promiscuity arising from off-target effects, comment on drug repurposing.
- 16 . Designed mutiple ligands. An emerging drug discovery paradigm. J. Med. Chem. 48(21), 6523–6543(2005).
- 17 . How to design muti-target drugs: target search options in cellular networks. Expert Opin. Drug Discov. 2(6), 799–808 (2007).
- 18 . A perspective on multi-target drug discovery and design for complex diseases. Clin. Transl. Med. 7, 3 (2018). •• Review of recent advance in the multi-target drug discovery for the treatment of the complex disease.
- 19 . Polypharmacology in drug development: a minireview of current technologies. ChemMedChem 11(12), 1211–1218 (2016).
- 20 . Drug Selectivity An Evolving Concept In Medicinal Chemistry. Wiley VCH Verlag GmbH & Co KGaA, Weinheim, Germany, 161–206 (2018).
- 21 . Phenotypic screening in the 21st century. Front. Pharmacol. 5, 264 (2014).
- 22 . Next generation phenotypic screening. Future Med. Chem. 8(11), 1331–1347 (2016).
- 23 . Targeting nicotine addiction: the possibility of a therapeutic vaccine. Drug Des. Dev. Ther. 5, 211–224 (2011).
- 24 N-(omega-(4-(2-methoxyphenyl)piperazin-1-yl)alkyl)carboxamides as dopamine D2 and D3 receptor ligands. J. Med. Chem. 46(18), 3883–3899 (2003).
- 25 Cyclohexylcarbamic acid 3’- or 4’-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure-activity relationships, and molecular modeling studies. J. Med. Chem. 47(21), 4998–5008 (2004).
- 26 Applying a multitarget rational drug design strategy: the first set of modulators with potent and balanced activity toward dopamine D3 receptor and fatty acid amide hydrolase. Chem. Commun. 50(38), 4904–4907 (2014).
- 27 . Dopamine D3 receptor antagonists as therapeutic agents. Drug Discov. Today 10(13), 917–925 (2005).
- 28 Can we discover pharmacological promiscuity early in the drug discovery process? Drug Discov. Today 17(7–8), 325–335 (2012). • This review mainly discusses the trends in the assessment of pharmacological promiscuity and proposes some strategies to enable early detection and mitigation.
- 29 . Charting the chemical space around the (iso)indoline scaffold, a comprehensive approach towards multitarget directed ligands. Bioorg. Med. Chem. Lett. 26(17), 4211–4215 (2016).
- 30 Design and synthesis of janus kinase 2 (JAK2) and histone deacetlyase (HDAC) bispecific inhibitors based on pacritinib and evidence of dual pathway inhibition in hematological cell lines. J. Med. Chem. 59(18), 8233–8262 (2016).
- 31 . 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. J. Med. Chem. 60(13), 5290–5305 (2017).
- 32 . Designing multiple ligands-medicinal chemistry strategies and challenges. Curr. Pharm. Design 15(6), 587–600 (2009).
- 33 A 1.5-megabase yeast artificial chromosome contig from human chromosome 10q11.2 connecting three genetic loi (Ret, D10S94, and D10S102) closely linked to MEN2A locus. Proc. Natl Acad. Sci. USA 90(2), 492–496 (1993).
- 34 . Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature 486(7401), 80–84 (2012).
- 35 Polypharmacology of N6-(3-Iodobenzyl)adenosine-5′-N-methyluronamide (IB-MECA) and related A3 Adenosine receptor ligands: peroxisome proliferator activated receptor (PPAR) γ partial agonist and PPARδ antagonist activity suggests their antidiabetic potential. J. Med. Chem. 60(17), 7459–7475 (2017).
- 36 . New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem. 53(7), 2719–2740 (2010).
- 37 . Highly promiscuous small molecules from biological screening assays include many pan-assay interference compounds but also candidates for polypharmacology. J. Med. Chem. 59(22), 10285–10290 (2016). •• Provides a way to obtain the leads for further exploring multi-target activities and the molecular basis of polypharmacology.
- 38 . Repurposing strategies for tropical disease drug discovery. Bioorg. Med. Chem. Lett. 26(11), 2569–2576 (2016). •• This digest describes applications of different repurposing approaches for neglected tropical diseases.
- 39 . Drug target identification using side-effect similarity. Science 321(5886), 263–266 (2008).
- 40 . Drug repurposing to target Ebola virus replication and virulence using structural systems pharmacology. BMC Bioinformatics 17, 90 (2016).
- 41 . Drug repositioning by structure-based virtual screening. Chem. Soc. Rev. 42(5), 2130–2141 (2013).
- 42 A safe lithium mimetic for bipolar disorder. Nat. Commun. 4, 1332–1338 (2013).
- 43 . NIH Molecular Libraries Initiative. Science 306(5699), 1138–1139 (2004).
- 44 . Epithelial to mesenchymal transition (EMT) biomarkers--E-cadherin, beta-catenin, APC and Vimentin--in oral squamous cell carcinogenesis and transformation. Oral. Oncol. 48(10), 997–1006 (2012).
- 45 Axitinib blocks Wnt/beta-catenin signaling and directs asymmetric cell division in cancer. Proc. Natl Acad. Sci. USA 113(33), 9339–9344 (2016).
- 46 . Interleukin-6 and its receptor: a paradigm for cytokines. Science 258(5082), 593–597 (1992).
- 47 Fragment-based drug design and drug repositioning using multiple ligand simultaneous docking (MLSD), identifying celecoxib and template compounds as novel inhibitors of signal transducer and activator of transcription 3 (STAT3). J. Med. Chem. 54(15), 5592–5596 (2011).
- 48 Drug design targeting protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning: discovery of raloxifene and bazedoxifene as novel inhibitors of IL-6/GP130 interface. J. Med. Chem. 57(3), 632–641 (2014).
- 49 . Target repurposing for neglected disease. Future Med. Chem. 3(10), 1307–1315 (2011). • Describes the overarching strategy of target repurposing as a tool for initiating and prosecuting neglected disease drug discovery programs.
- 50 . Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi. BMC Genomics 6, 127 (2005).
- 51 . Aurora kinase homologue is involved in regulating both mitosis and cytokinesis in Trypanosoma brucei. J. Biol. Chem. 281(14), 9677–9687 (2006).
- 52 The human Aurora kinase inhibitor danusertib is a lead compound for anti-trypanosomal drug discovery via target repurposing. Eur. J. Med. Chem. 62, 777–784 (2013).
- 53 Kinase scaffold repurposing for neglected disease drug discovery: discovery of an efficacious, lapatinib-derived lead compound for trypanosomiasis. J. Med. Chem. 56(10), 3820–3832 (2013).
- 54 . Strategy of molecular drug design: activity and druggability. Acta Pharm. Sin. 45(5), 539–547 (2010).
- 55 Reducing safety-related drug attrition: the use of in vitro pharmacological profiling. Nat. Rev. Drug Discov. 11(12), 909–922 (2012).
- 56 Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 102(23), 2836–2841 (2000).
- 57 . Synthesis of novel analogs of cabergoline: improving cardiovascular safety by removing 5-HT2B receptor agonism. ACS Med. Chem. Lett. 4(2), 254–258 (2013).
- 58 Removal of human ether-a-go-go related gene (hERG) K+ channel affinity through rigidity: a case of clofilium analogues. J. Med. Chem. 56(23), 9427–9440 (2013).
- 59 . Application of amide bioisosteres in the optimization of lead compounds. Prog. Chem. 28(9), 1406–1416 (2016).
- 60 Discovery of CXCR3 antagonists substituted with heterocycles as amide surrogates: improved PK, hERG and metabolic profiles. Bioorg. Med. Chem. Lett. 24(4), 1085–1088 (2014).
- 61 Identification of potential off-target toxicity liabilities of catechol-o-methyltransferase inhibitors by differential competition capture compound mass spectrometry. J. Med. Chem. 59(10), 4664–4675 (2016).
- 62 Capture compound mass spectrometry: a technology for the investigation of small molecule protein interactions. Assay Drug Dev. Technol. 5(3), 381–390 (2007).
- 63 . Navigating the chemical space of multi-target directed ligands: from hybrids to fragments in Alzheimer's disease. Molecules 21(4), 466–477 (2016).