Advantages of Ligand Design in Multi-Target Therapy: A Solution to Side Effects

1. 1. θεωρία της υβριδοποίησης,2.Αρχή της multi-target θεωρίας3. Ligand Design

3. “one drug, one target” το πλεονέκτημα: είναι η έλλειψη των εκτός στόχου παράπλευρων δράσεων

4. Τα In vitro αποτελέσματα δεν συμβαδίζουν με τα In vivo στα single targets drugs

5. One drug-many targets

7. Polypharmacology: ποια είναι η αιτία της ανάπτυξης της? • H πολυπλοκότητα των ασθενειών δημιούργησε το ενδιαφέρον για την ανάπτυξη της πολυφαρμακολογίαςκαι της multitarget/multifunctional therapy. • Η πολυφαρμακολογία υποστηρίζει ότι πολλά δραστικά μόρια μπορούν να δράσουν σε πολλαπλούς στόχους. • Φάρμακα με δράση σε πολλαπλούς στόχους οδηγούν σε ανώτερο θεραπευτικό αποτέλεσμα μειώνοντας τις ανεπιθύμητες ενέργειες. • Στις πολύπλοκες/πολυπαραγοντικές ασθένειες περιλαμβάνονται : • O καρκίνος, AIDs, οι νευροεκφυλίσεις, αθηρωσκλήρυνση, κατάθλιψη και οι φλεγμονώδους προέλευσης ασθένειες.

8. Νέο ή παλιό? • Snake and spider venoms are bothmulti-component systems, and plants also developed a combinative-strategy to defend themselves againstpathogens. • Παραδοσιακά φάρμακα και συνταγές • Παλιά φάρμακα (salicylate, non-steroidal anti-inflammatory drugs (NSAIDs), metformin, antidepressants,anti-neurodegenerative agents, multi-target kinase inhibitors (such as Gleevec™, the inhibitorsof the kinase-maturating molecular chaperone, Hsp90)

9. Single targets? • Πιθανά να διαθέτουν “back-up” συστήματα που είναι αρκετά διαφορετικά ώστε το φάρμακο να μην μπορεί να έχει θεραπευτικό αποτέλεσμα

10. Η ανακάλυψη νέων φαρμάκων στον 21ο αιώνα…. • Αντιμετωπίζει το μειονέκτημα της εισόδου νέων φαρμάκων στην κλινική έρευνα. • Multitarget 16% πριν το 2015 21 + 10 = 31%

11. Η πρόκληση: • α) νέοι στόχοι, β) ταυτοποίηση φαρμάκων και γ) ορθολογικός σχεδιασμός

12. Εργαλεία: Two networks the target–target drug–drug networks the target–target drug–drug networks

13. Βιβλιοθήκη υβριδικών μορίων Ligand design 10 πρωτεϊνικά μοντέλα LOX Εικονική ανάλυση (virtual screening) Τιμές λειτουργικής βαθμολόγησης (scoring function values). Επιλογή μοντέλων Επιλογή νέων μορίων για σύνθεση AutodockVina v.1.1.1. The Scripps Research Institute PyRx program, USA UCSF Chimera software v.1.5.3. Regents of the University of California, USA AnteChamber Python Parser interface (ACPYPE) tool Toolkit GROMACS

14. Rational design of multi-target compounds

15. Schematic representation of the QSAR workflow

16. the prototype of the third-generationof antipsychotics, aripiprazole, launched into the marketin 2015, was the first designed serotonin-dopamineactivity modulator (SDAM). • However, it also displayedunwanted side effects, probably arising from a sustainedinteraction with post-synaptic D2receptors • Brexpiprazolewas licensed on October 2015 as a novel D2and 5-HT1A partial agonist, with less intrinsic activityat D2receptors and more balanced activities at 5-HT2A,5-HT1A, and α1B receptor subtypes than aripiprazole

17. a profile of partial agonism at D2 αndD3receptors • cariprazine, approved bythe FDA in September 2015 for the treatment of schizophreniaand bipolar disorders.

18. νευροεκφυλιστικά • Safinamide, 2017, • Αντισπασμωδικό • MAO-B and dopamine reuptake • Rasagiline, 2006

19. αντικαρκινικά • Μulti- kinases inhibitors Neratinib Lenvatinib multi-tyrosine kinase inhibitor

20. Multifunctional drugs: a novel concept for psychopharmacology. • Multifunctional drugs include those agents with more than one putative therapeutic mechanism of action

21. Multifunctional Drugs for Head Injury • Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide in individuals under the age of 45 years, and, despite extensive efforts to develop neuroprotective therapies, there has been no successful outcome in any trial of neuroprotection to date. • Statins, progesterone,erythropoietin,cyclosporine,dexanabinol,bradykinin, substance P,minocycline, thyrotropin releasing hormone 

22. Tacrineand donepezil derivatives as potential multifunctional drugs against Alzheimer’s disease

23. Antimicrobial Peptides: Multifunctional Drugs for Different Applications • They are characterized by antibiotic, antifungal and antiviral activities against a variety of microorganisms. • In addition to their role as endogenous antimicrobials, APs participate in multiple aspects of immunity. They are involved in septic and non-septic inflammation, wound repair, angiogenesis, regulation of the adaptive immune system and in maintaining homeostasis. Due to those characteristics AP could play an important role in many practical applications.

24. The 21 multi-target drugs and 10 therapeutic combinations approved in 2015–2017 organized according to their Anatomical TherapeuticChemical (ATC) Classification System

25. Υβριδικά μόρια- Ανάγκη ανάπτυξής τους • Ο συνήθης τρόπος αντιμετώπισης πολυπαραγοντικών ασθενειών αποτελεί η χορήγηση περισσοτέρων του ενός φαρμάκων. • Συνδυασμός δύο φαρμακοφόρων ομάδων (Α,Β) σε ένα ενιαίο κοινό μόριο, στοχεύει στην δημιουργία μιας νέας χημικής οντότητας βιολογικά δραστικότερης (υβριδικό μόριο)

26. Πλεονεκτήματα τεχνικής μοριακής υβριδοποίησης: • δημιουργία πολλαπλών προσδετών με φαρμακοκινητικά πλεονεκτήματα • ενεργοποίηση διαφορετικών στόχων από ένα μόνο ενιαίο φαρμακομόριο • αλλαγή προφίλ βιοδιαθεσιμότητας • εύκολη και αποτελεσματική απέκκριση

29. Το benorylate αποτελεί το πρώτο γνωστό υβριδικό φαρμακευτικό σκεύασμα της Παρακεταμόλης (ασπιρίνη + παρακεταμόλη) benorylate

30. Χαρακτηριστικά παραδείγματα υβριδικών ενώσεων • Lima, L.M.; Castro, P.; Machado, A.L.; Fraga, C.A.M.; Lugnier, C.; Moraes, V.L.G.; Barreiro, E.J. Bioorg. Med. Chem. 10 (2002) 3067-3073 • Kartasasmita, R.E.; Laufer, S.; Lehmann, J. Arch. Pharm. (Weinheim)335 (2002) 363-366 • Santos, J.L.; Yamasaki, P.R.; Chung, M.C.; Takashi, C.H.; Pavan, F.R.; Leite, C.Q. Bioorg.Med. Chem. 17 (2009) 3795-3799.

31. Hybrid drugs for malaria hybrids of (i) artemisinins or other endoperoxide-based agents and quinolines (e.g. trioxaquines), (ii) chloroquine or other aminoquinolines and resistance-reversing or other agents, and (iii) peptidase inhibitors and other agents. 

33. Εμπορικά διαθέσιμα υβριδικά φάρμακα

34. potential HIV/malaria hybrids hybrid molecules to target Plasmodium falciparum and HIV simultaneously for a potential HIV/malaria combination therapy. Hybrid molecules were synthesized by the covalent fusion of azidothymidine (AZT) with dihydroartemisinin (DHA), a tetraoxane or a 4-aminoquinoline derivative

37. hybrid anticancer drugs Hybrid anticancer drugs are of great therapeutic interests as they can potentially overcome most of the pharmacokinetic drawbacks encountered when using conventional anticancer drugs. In fact, the future of hybrid anticancer drugs is very bright for the discovery of highly potent and selective molecules that triggers two or more cytocidal pharmacological mechanisms of action acting in synergy to inhibit cancer tumor growth. DNA alkylating agent hybrids (e.g., platinum(II), nitrogen mustard, etc.), vitamin-D receptor, agonist-histone deacetylase inhibitors, combi-molecule therapies and other types of hybrid anticancer agents

39. Tacrine NO donors

41. Χαρακτηριστικά παραδείγματα υβριδικών ενώσεων PriscilaLonghinBosquesiet al., Pharmaceuticals 4 (2011) 1452

42. Hybrid Drugs as Potential Combatants Against Drug-Resistant Microbes Antimicrobial resistance to drugs is a serious threat to public health. Different strategies have been adopted to deal with antimicrobial resistance to known drugs: one such strategy is the use of drug hybrids; this is a promising strategy to address the growing problem of drug resistance. recently examples of combining (hybrid) two standard drugs in a single molecule for combating antibiotic-resistant microorganisms are given, and to present evidence supporting that drug hybrids are the urgent and practical solution to stop or slow down the spread of drug resistance

43. Millions to develop multi-functional drugs • Professor Kurt V. Gothelf has received DKK 60 million from the Novo Nordisk Foundation Challenge Programme to establish the Center for Multifunctional Biomolecular Drug Design (CEMBID) at the Interdisciplinary Nanoscience Center (iNANO) at Aarhus University.

44. Most drugs used today only have one mechanism of action, and it is both difficult and expensive to manufacture drugs with several function. The researchers behind the Center for Multifunctional Biomolecular Drug Design (CEMBID) therefore want to find new ways of conjugating drugs in order to achieve multiple mechanisms of action. Researchers at the centredevelop a number of new methods to chemically bind medically relevant biological molecules. Nucleic acids such as DNA that contain all the information necessary to create and maintain life can be coded in the laboratory to conjugate themselves into very well-defined microscopic 2D or 3D structures. When these nucleic acid structures are attached to medically relevant proteins and small molecules, it is possible to link both existing and new drugs simply and efficiently to create multifunctional drugs. Among other things, these new drugs could be developed to be able to cross the body's barriers, influence the immune system in a specific direction, bind to the cells that require treatment, and then release the  medicine to them.