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Racionalno Načrtovanje Potencialnih Antidepresivov Iz Skupine Reverzibilnih Inhibitorjev Monoamin-Oksidaze A

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Racionalno Načrtovanje Potencialnih Antidepresivov Iz Skupine Reverzibilnih Inhibitorjev Monoamin-Oksidaze A Diplomsko delo Racionalno načrtovanje potencialnih antidepresivov iz skupine reverzibilnih inhibitorjev monoamin-oksidaze A Junij, 2017 Marko Breznik Marko Breznik Racionalno načrtovanje potencialnih antidepresivov iz skupine reverzibilnih inhibitorjev monoamin-oksidaze A Diplomsko delo Maribor, 2017 Racionalno načrtovanje potencialnih antidepresivov iz skupine reverzibilnih inhibitorjev monoamin-oksidaze A Diplomsko delo univerzitetnega študijskega programa I. stopnje Študent: Marko Breznik Študijski program: univerzitetni študijski program I. stopnje Kemija Predvideni strokovni naslov: diplomirani kemik (UN) Mentor: izr. prof. dr. Urban Bren Komentor: dr. Janez Konc Maribor, 2017 Racionalno načrtovanje potencialnih antidepresivov iz skupine RIMA Kazalo .......................................................................................................................................... IV Kazalo................................................................................................................................... I Izjava .................................................................................................................................. II Zahvala .............................................................................................................................. III Povzetek ............................................................................................................................ IV Abstract .............................................................................................................................. V Seznam tabel ...................................................................................................................... VI Seznam slik ....................................................................................................................... VII Uporabljeni simboli in kratice ......................................................................................... VIII 1 Uvod in opredelitev problema ....................................................................................... 1 2 Teoretični del ................................................................................................................ 3 2.1 Mehanizem delovanja antidepresivov ..................................................................... 3 2.2 Biokemija monoaminov ......................................................................................... 6 2.2.1 Zaviralci monoamin-oksidaze ......................................................................... 8 2.3 Harmala alkaloidi ................................................................................................... 9 2.3.1 Derivati harmina kot RIMA .......................................................................... 10 2.4 Racionalno načrtovanje učinkovin ........................................................................ 13 2.4.1 Smernice - farmakodinamika ........................................................................ 13 2.4.2 Smernice - farmakokinetika .......................................................................... 14 3 Eksperimentalni del..................................................................................................... 15 3.1 Načrtovanje na osnovi znanega liganda ................................................................ 15 3.1.1 Postopek (program LiSiCA) .......................................................................... 16 3.2 Načrtovanje na osnovi strukture tarčnega proteina ................................................ 17 3.2.1 Ovrednotenje rezultatov programa LiSiCA (program ProBiSdock) ............... 19 3.2.2 Iskanje ligandov na osnovi podobnosti vezavnih mest (program ProBiS) ...... 20 4 Rezultati in diskusija ................................................................................................... 21 4.1 Spojine pridobljene s programoma LiSiCA in ProBiSdock ................................... 21 4.1.1 Ocena farmakokinetičnih lastnosti................................................................. 22 4.1.2 Ocena farmakodinamičnih lastnosti ............................................................... 22 4.2 Derivati harmina .................................................................................................. 23 4.2.1 Lipofilni žepek (R7 derivati) .......................................................................... 23 4.2.2 Heteroatomi fragmentov v lipofilnem žepku ................................................. 25 4.2.3 Primerjava z znanimi RIMA ......................................................................... 26 4.2.4 R6 derivati β-karbolina .................................................................................. 27 4.3 Spojine pridobljene s programom ProBiS ............................................................. 28 4.4 Ocena zanesljivosti sidranja ................................................................................. 28 5 Zaključek .................................................................................................................... 29 6 Literatura .................................................................................................................... 31 7 Priloge ........................................................................................................................ 35 7.1 Tabela najboljših 100 ujemanj glede na oceno vezavne energije ........................... 35 8 Življenjepis ................................................................................................................. 41 Izjava o istovetnosti tiskane in elektronske verzije.............................................................. 43 I Racionalno načrtovanje potencialnih antidepresivov iz skupine RIMA Izjava Izjavljam, da sem diplomsko delo izdelal sam, prispevki drugih so posebej označeni. Pregledal sem literaturo s področja diplomskega dela po naslednjih geslih: Vir: Google Scholar (http://scholar.google.si/) Gesla: Število referenc Harmine 9 230 Harmala IN MAO 4 570 Carboline IN MAO 10 100 MAOI 22 400 Moclobemide IN harmine 508 Peganum harmala 9 840 Vir: UM:NIK univerzitetni iskalnik (http://www.ukm.um.si/) Gesla: Število referenc Monoamine oxidase IN reversible 20 553 Harmine IN RIMA 41 Moclobemide 9 771 Vir: COBISS+ (https://plus.si.cobiss.net/opac7/bib/search) Gesla: Število referenc Antidepressants (le knjige) 46 Pharmacology (le knjige) 6 123 Drug design (le knjige) 2 215 Medicinal chemistry (le knjige) 376 Skupno število pregledanih člankov: 84 Skupno število pregledanih knjig: 15 Maribor, junij 2017 Marko Breznik II Racionalno načrtovanje potencialnih antidepresivov iz skupine RIMA Zahvala Iskreno se zahvaljujem mentorju, izr. prof. dr. Urbanu Brenu, za strokovno usmerjanje, dosegljivost in zaupanje v moje sposobnosti ter Fakulteti za kemijo in kemijsko tehnologijo za vzpodbujanje samostojnosti pri pripravi teme diplomske naloge. Zahvala Kemijskem inštitutu, v sklopu katerega so bili ustvarjeni računalniški programi in ki mi je omogočil opravljanje diplomske naloge v svojih prostorih. Še posebej se zahvaljujem somentorju, dr. Janezu Koncu, za vodstvo, zaupanje v diplomsko temo ter sprotno podporo ter dr. Samu Lešniku in Blažu Škrlju za vse koristne informacije in pomoč pri programiranju. Rad bi se zahvalil še staršema za finančno in moralno podporo ter vsem prijateljem, dodatno Luciji Fleisinger in Vesni Gorenjak za nasvete ter Alini Holntaner in Maši Šraml, ki sta mi med opravljanjem diplomske naloge omogočili bivanje v Ljubljani. III Racionalno načrtovanje potencialnih antidepresivov iz skupine RIMA Racionalno načrtovanje potencialnih antidepresivov iz skupine reverzibilnih inhibitorjev monoamin-oksidaze A Povzetek Klinična depresija je poglaviten vzrok invalidnosti in pomemben dejavnik tveganja za samomor, ki je nadpovprečno pogost vzrok smrti v Sloveniji. Kljub zahtevnosti se motnja lahko zdravi uspešno in ima dobro prognozo. Antidepresivi se za zdravljenje depresije in drugih motenj uporabljajo vse pogosteje; navkljub obsežnim raziskavam pa za ta zdravila še vedno obstajajo številne možnosti izboljšav. Antidepresivi iz skupine reverzibilnih inhibitorjev monoamin-oksidaze A (RIMA) so bili doslej zapostavljeni zaradi pogostega enačenja s skupino antidepresivnih zdravil, ki so se na encim monoamin-oksidazo (MAO) vezali ireverzibilno in s tem povzročali smrtno nevarne interakcije s hrano. RIMA predstavljajo drugo generacijo antidepresivov z encimskim delovanjem in teh interakcij ne povzročajo, prav tako imajo bistveno zmanjšano tveganje interakcij z drugimi zdravili. Na osnovi dobre učinkovitosti, varnosti, ugodnega profila stranskih učinkov ter pomanjkanja predstavnikov te skupine na trgu, smo se v diplomskem delu osredotočili na racionalno načrtovanje antidepresivov tipa RIMA. Harmin je naravna spojina s tradicionalno rabo kot RIMA. Po strukturi predstavlja majhno, rigidno molekulo z dobro absorpcijo, penetracijo krvno-možganske pregrade in nanomolarno inhibitorno koncentracijo MAOA, vendar zaradi pomanjkanja selektivnosti delovanja povzroča številne stranske učinke. Reševanja problematike smo se lotili po treh pristopih. Zdravilom-podobne substance smo razvrstili po strukturni podobnosti derivatu harmina, ki tvori dodatne interakcije v lipofilnem žepku aktivnega mesta in ima in vitro izboljšano afiniteto za MAOA. Najbolj podobne molekule smo sidrali v tarčo in jih razvrstili po oceni vezavne energije. Kot rezultat prvega pristopa navajamo 100 tarči najbolje prilegajočih se molekul, za katere
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