335
Views
5
CrossRef citations to date
0
Altmetric
Perspective

What are the challenges with multi-targeted drug design for complex diseases?

, , & ORCID Icon
Pages 673-683 | Received 24 Nov 2021, Accepted 28 Apr 2022, Published online: 12 May 2022

References

  • Al-Ali H. The evolution of drug discovery: from phenotypes to targets, and back. MedChemComm. 2016;7(5):788–798.
  • Zhang Q, Fu Q, Bai X, et al. Molecular profiling-based precision medicine in cancer: a review of current evidence and challenges. Front Oncol. 2020;10:532403.
  • Laes J-F, Aftimos P, Barthelemy P, et al. The clinical impact of using complex molecular profiling strategies in routine oncology practice. Oncotarget. 2018;9(29):20282–20293.
  • Malone ER, Oliva M, Sabatini PJB, et al. Molecular profiling for precision cancer therapies. Genome Med. 2020;12(1):8.
  • Mitchell KJ. What is complex about complex disorders? Genome Biol. 2012;13(1):237.
  • Gourie-Devi M. Epidemiology of neurological disorders in India: review of background, prevalence and incidence of epilepsy, stroke, Parkinson’s disease and tremors. Neurol India. 2014;62(6):588–598.
  • Armstrong MJ, Okun MS. Diagnosis and treatment of Parkinson disease: a review. JAMA. 2020;323(6):548–560.
  • Association EPD What is Parkinson’s? [Internet]. [cited 2021 Nov 16]. Available from: https://www.epda.eu.com/about-parkinsons/what-is-parkinsons/.
  • Dorsey ER, Elbaz A, Nichols E, GBD 2016. Parkinson’s disease collaborators. Global, regional, and national burden of Parkinson’s disease, 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2018;17(11):939–953.
  • Zahoor I, Shafi A, Haq E Pharmacological Treatment of Parkinson’s disease [internet]. Park. Dis. Pathog. Clin. Asp. Internet. Codon Publications; 2018 [cited 2021 Nov 17]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK536726/.
  • Stępnicki P, Kondej M, Kaczor AA. Current concepts and treatments of schizophrenia. Molecules. 2018;23(8):2087.
  • Santomauro DF, Herrera AMM, Shadid J, et al. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. Lancet. 2021;398(10312):1700–1712.
  • Kamenov K, Twomey C, Cabello M, et al. The efficacy of psychotherapy, pharmacotherapy and their combination on functioning and quality of life in depression: a meta-analysis. Psychol Med. 2017;47(3):414–425.
  • Dementia [Internet]. [cited 2021 Nov 16]. Available from: https://www.who.int/news-room/fact-sheets/detail/dementia.
  • 2020 Alzheimer’s disease facts and figures. Alzheimers Dement. 2020;16:391–460. DOI:https://doi.org/10.1002/alz.12068.
  • Marotta G, Basagni F, Rosini M, et al. Memantine derivatives as multitarget agents in Alzheimer’s disease. Mol Basel Switz. 2020;25:E4005.
  • Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes Atlas, 9th edition. Diabetes Res Clin Pract Internet].cited 2021 Nov 16; Available from.;2019 157:107843.
  • Otto-Buczkowska E, Jainta N. Pharmacological treatment in diabetes mellitus type 1 – insulin and what else? Int J Endocrinol Metab. 2017;16(1):e13008.
  • Pfeiffer AFH, Klein HH. The treatment of type 2 diabetes. Dtsch Ärztebl Int. 2014;111(5):69–82.
  • Strebhardt K, Ullrich A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat Rev Cancer. 2008;8(6):473–480.
  • Li MC, Hertz R, Bergenstal DM. Therapy of choriocarcinoma and related trophoblastic tumors with folic acid and purine antagonists. N Engl J Med. 1958;259(2):66–74.
  • Lu D-Y, Wu H-Y, Yarla NS, et al. HAART in HIV/AIDS treatments: future trends. Infect Disord Drug Targets. 2018;18(1):15–22.
  • Preer S, Dunkel M, Hoffmann MF, et al. drug cocktail optimization in chemotherapy of cancer. PLOS ONE. 2012;7(12):e51020.
  • Masnoon N, Shakib S, Kalisch-Ellett L, et al. What is polypharmacy? A systematic review of definitions. BMC Geriatr. 2017;17(1):230.
  • Casas AI, Hassan AA, Larsen SJ, et al. From single drug targets to synergistic network pharmacology in ischemic stroke. Proc Natl Acad Sci. 2019;116(14):7129–7136.
  • Xiong Z, Jeon M, Allaway RJ, et al. Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: the multi-targeting drug DREAM challenge. PLOS Comput Biol. 2021;17(9):e1009302.
  • Talevi A. Multi-target pharmacology: possibilities and limitations of the “skeleton key approach” from a medicinal chemist perspective. Front Pharmacol. 2015;6:205.
  • Espinoza-Fonseca LM. The benefits of the multi-target approach in drug design and discovery. Bioorg Med Chem. 2006;14(4):896–897.
  • Ramsay RR, Popovic-Nikolic MR, Nikolic K, et al., A perspective on multi-target drug discovery and design for complex diseases. Clin Transl Med. 7(1): 3. 2018.
  • Markou A, Unger L, Abir-Awan M, et al. Molecular mechanisms governing aquaporin relocalisation. Biochim Biophys Acta Biomembr. 2021;1864(4):183853.
  • Salman MM, Kitchen P, Yool AJ, et al. Recent breakthroughs and future directions in drugging aquaporins. Trends Pharmacol Sci. 2022;43(1):30–42.
  • Zhou J, Jiang X, He S, et al., Rational design of multitarget-directed ligands: strategies and emerging paradigms. J Med Chem. 62(20): 8881–8914. 2019.
  • Omar YM, Abdu-Allah HHM, Abdel-Moty SG. Synthesis, biological evaluation and docking study of 1,3,4-thiadiazole-thiazolidinone hybrids as anti-inflammatory agents with dual inhibition of COX-2 and 15-LOX. Bioorg Chem. 2018;80:461–471.
  • Murugesan N, Gu Z, Fadnis L, et al. Dual angiotensin II and endothelin A receptor antagonists:  synthesis of 2‘-substituted N-3-isoxazolyl biphenylsulfonamides with improved potency and pharmacokinetics. J Med Chem. 2005;48(1):171–179.
  • Kalash L, Val C, Azuaje J, et al. Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases. J Cheminformatics. 2017;9(1):67.
  • Zhuang T, Xiong J, Hao S, et al. Bifunctional μ opioid and σ1 receptor ligands as novel analgesics with reduced side effects. Eur J Med Chem. 2021;223:113658.
  • Hazarika RR, Sostaric N, Sun Y, et al. Large-scale docking predicts that sORF-encoded peptides may function through protein-peptide interactions in Arabidopsis thaliana. PLOS ONE. 2018;13(10):e0205179.
  • Huang H, Zhang G, Zhou Y, et al. Reverse screening methods to search for the protein targets of chemopreventive compounds. Front Chem. 2018;6:138.
  • Grosdidier A, Zoete V, Michielin O. SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic Acids Res. 2011;39(suppl):W270–W277.
  • Santos KB, Guedes IA, Karl ALM, et al. Highly flexible ligand docking: benchmarking of the dockthor program on the LEADS-PEP protein–peptide data set. J Chem Inf Model. 2020;60(2):667–683.
  • Sun H, Shen Y, Luo G, et al. An integrated strategy for identifying new targets and inferring the mechanism of action: taking rhein as an example. BMC Bioinformatics. 2018;19(1):315.
  • Doman TN, McGovern SL, Witherbee BJ, et al. Molecular docking and high-throughput screening for novel inhibitors of protein tyrosine phosphatase-1B. J Med Chem. 2002;45(11):2213–2221.
  • Moumbock AFA, Li J, Mishra P, et al. Current computational methods for predicting protein interactions of natural products. Comput Struct Biotechnol J. 2019;17:1367–1376.
  • Liu X, Ouyang S, Yu B, et al. PharmMapper server: a web server for potential drug target identification using pharmacophore mapping approach. Nucleic Acids Res. 2010;38(suppl_2):W609–W614.
  • Vlachakis D, Fakourelis P, Megalooikonomou V, et al. DrugOn: a fully integrated pharmacophore modeling and structure optimization toolkit. PeerJ. 2015;3:e725.
  • Yang H, Ding Y, Tang J, et al. Identifying potential association on gene-disease network via dual hypergraph regularized least squares. BMC Genomics. 2021;22(1):605.
  • Asif M, Martiniano HFMCM, Vicente AM, et al. Identifying disease genes using machine learning and gene functional similarities, assessed through gene ontology. PLOS ONE. 2018;13(12):e0208626.
  • Kandoi G, Acencio ML, Lemke N. Prediction of druggable proteins using machine learning and systems biology: a mini-review. Front Physiol. 2015;6:366.
  • Tang J, Aittokallio T. Network pharmacology strategies toward multi-target anticancer therapies: from computational models to experimental design principles. Curr Pharm Des. 2014;20(1):20–36.
  • Jumper J, Evans R, Pritzel A, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596(7873):583–589.
  • Svetnik V, Liaw A, Tong C, et al. random forest:  a classification and regression tool for compound classification and QSAR modeling. J Chem Inf Comput Sci. 2003;43(6):1947–1958.
  • Chakravarti SK, Alla SRM. Descriptor free QSAR modeling using deep learning with long short-term memory neural networks. Front Artif Intell. 2019;2:17.
  • Griffen EJ, Dossetter AG, Leach AG, et al. Can we accelerate medicinal chemistry by augmenting the chemist with big data and artificial intelligence? Drug Discov Today. 2018;23(7):1373–1384.
  • Halder AK, Dias Soeiro Cordeiro MN. QSAR-Co-X: an open source toolkit for multitarget QSAR modelling. J Cheminformatics. 2021;13(1):29.
  • Vamathevan J, Clark D, Czodrowski P, et al. Applications of machine learning in drug discovery and development. Nat Rev Drug Discov. 2019;18(6):463–477.
  • Lavecchia A. Deep learning in drug discovery: opportunities, challenges and future prospects. Drug Discov Today. 2019;24(10):2017–2032.
  • Miller ML, Molinelli EJ, Nair JS, et al. Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets. Sci Signal. 2013;6(294):ra85–ra85.
  • Pushpakom S, Iorio F, Eyers PA, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019;18(1):41–58.
  • Das J. Repurposing of Drugs–The Ketamine Story. J Med Chem. 2020;63(22):13514–13525.
  • Kitchen P, Salman MM, Halsey AM, et al. Targeting aquaporin-4 subcellular localization to treat central nervous system edema. Cell. 2020;181(4):784–799.e19.
  • Sylvain NJ, Salman MM, Pushie MJ, et al. The effects of trifluoperazine on brain edema, aquaporin-4 expression and metabolic markers during the acute phase of stroke using photothrombotic mouse model. Biochim Biophys Acta Biomembr. 2021;1863(5):183573.
  • Swinney DC. Biochemical mechanisms of drug action: what does it take for success? Nat Rev Drug Discov. 2004;3(9):801–808.
  • Wevers NR, Kasi DG, Gray T, et al. A perfused human blood-brain barrier on-a-chip for high-throughput assessment of barrier function and antibody transport. Fluids Barriers CNS. 2018;15(1):23.
  • Salman MM, Marsh G, Kusters I, et al. Design and validation of a human brain endothelial microvessel-on-a-chip open microfluidic model enabling advanced optical imaging. Front Bioeng Biotechnol. 2020;8:573775.
  • Venkataraman L, Fair SR, McElroy CA, et al. Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer’s disease. Stem Cell Rev Rep. 2020;18(2):696–717.
  • Proschak E, Stark H, Merk D. Polypharmacology by design: a medicinal chemist’s perspective on multitargeting compounds. J Med Chem. 2019;62(2):420–444.
  • Morphy R, Kay C, Rankovic Z. From magic bullets to designed multiple ligands. Drug Discov Today. 2004;9(15):641–651.
  • Richard Morphy J. Chapter 10 the challenges of multi-target lead optimization. Des multi-target drugs. Cambridge: The Royal Society of Chemistry; 2012. p. 141–154. DOI: https://doi.org/10.1039/9781849734912-00141.
  • Bolognesi ML. Polypharmacology in a single drug: multitarget drugs. Curr Med Chem. 2013;20(13):1639–1645.
  • Morphy R, Rankovic Z. Designing multiple ligands - medicinal chemistry strategies and challenges. Curr Pharm Des. 2009;15(6):587–600.
  • Costantino L, Barlocco D. Designed multiple ligands: basic research vs clinical outcomes. Curr Med Chem. 2012;19(20):3353–3387.
  • Ma H, Huang B, Zhang Y. Recent advances in multitarget-directed ligands targeting G-protein-coupled receptors. Drug Discov Today. 2020;25(9):1682–1692.
  • Bolognesi ML. Harnessing Polypharmacology with medicinal chemistry. ACS Med Chem Lett. 2019;10(3):273–275.
  • Morphy R, Rankovic Z. Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005;48(21):6523–6543.
  • Morphy JR. Chapter 10: the challenges of multi-target lead optimization. Des Multi-Target Drugs [Internet]. 2012 [cited 2021 Nov 14]. p. 141–154. Available from: https://pubs.rsc.org/en/content/chapter/bk9781849733625-00141/978-1-84973-362-5.
  • Long JM, Holtzman DM. Alzheimer disease: an Update on pathobiology and treatment strategies. Cell. 2019;179(2):312–339.
  • Benek O, Korabecny J, Soukup O. A perspective on multi-target drugs for Alzheimer’s disease. Trends Pharmacol Sci. 2020;41(7):434–445.
  • Zhang C, Du Q-Y, Chen L-D, et al. Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer’s disease. Eur J Med Chem. 2016;116:200–209.
  • Barbosa FAR, Canto RFS, Saba S, et al. Synthesis and evaluation of dihydropyrimidinone-derived selenoesters as multi-targeted directed compounds against Alzheimer’s disease. Bioorg Med Chem. 2016;24(22):5762–5770.
  • Chen Z, Digiacomo M, Tu Y, et al. Discovery of novel rivastigmine-hydroxycinnamic acid hybrids as multi-targeted agents for Alzheimer’s disease. Eur J Med Chem. 2017;125:784–792.
  • Ozadali-Sari K, Tüylü Küçükkılınç T, Ayazgok B, et al. Novel multi-targeted agents for Alzheimer’s disease: synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles. Bioorg Chem. 2017;72:208–214.
  • Cheong SL, Federico S, Spalluto G, et al. The current status of pharmacotherapy for the treatment of Parkinson’s disease: transition from single-target to multitarget therapy. Drug Discov Today. 2019;24(9):1769–1783.
  • Affini A, Hagenow S, Zivkovic A, et al. Novel indanone derivatives as MAO B/H3R dual-targeting ligands for treatment of Parkinson’s disease. Eur J Med Chem. 2018;148:487–497.
  • Carradori S, Ortuso F, Petzer A, et al. Design, synthesis and biochemical evaluation of novel multi-target inhibitors as potential anti-Parkinson agents. Eur J Med Chem. 2018;143:1543–1552.
  • Shao Y-M, Ma X, Paira P, et al. Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson’s disease treatment. PloS One. 2018;13(1):e0188212.
  • Aldewachi H, Al-Zidan RN, Conner MT, et al. High-throughput screening platforms in the discovery of novel drugs for neurodegenerative diseases. Bioeng Basel Switz. 2021;8. 30.
  • Salman MM, Al-Obaidi Z, Kitchen P, et al. Advances in applying computer-aided drug design for neurodegenerative diseases. Int J Mol Sci. 2021;22(9):4688.
  • Tran S, DeGiovanni P-J, Piel B, et al. Cancer nanomedicine: a review of recent success in drug delivery. Clin Transl Med. 2017;6(1):44.
  • Kenny RG, Marmion CJ. Toward multi-targeted platinum and ruthenium drugs—a new paradigm in cancer drug treatment regimens? Chem Rev. 2019;119(2):1058–1137.
  • Abdelsalam MA, AboulWafa OM, Badawey E-SA, et al. Design and synthesis of some β-carboline derivatives as multi-target anticancer agents. Future Med Chem. 2018;10(24):2791–2814.
  • Abdelazeem AH, El-Saadi MT, Said EG, et al. Novel diphenylthiazole derivatives with multi-target mechanism: synthesis, docking study, anticancer and anti-inflammatory activities. Bioorg Chem. 2017;75:127–138.
  • Wu J, Yang T, Wang X, et al. Development of a multi-target anticancer Sn(ii) pyridine-2-carboxaldehyde thiosemicarbazone complex. Dalton Trans. 2021;50(31):10909–10921.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.