Title Istraživanje strukturnih značajki, bioloških meta i ADMET svojstava retinoida Title (english) Study of structural features, biological targets and ADMET properties of retinoids Author Melita Delač Mentor Milena Jadrijević-Mladar Takač (mentor)Committee member Milena Jadrijević-Mladar Takač (predsjednik povjerenstva)Committee member Monika Barbarić (član povjerenstva)Committee member Irena Žuntar (član povjerenstva)Granter University of Zagreb Defense date and country 2016-09-30, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Abstract Istraživane su strukturne značajke retinoida primjenom različitih računalnih programa i
njihova poveznica s biološkim metama i ADMET svojstvima. Većine ispitivanih retinoida
odstupa od Lipinski ′pravila 5′ zbog lipofilnosti ovih molekula što se odražava u smanjenoj
oralnoj apsorpciji i bioraspoloživosti. Mehanizam djelovanja retinoida podrazumijeva vezanje
na nuklearne receptore koji djeluju kao transkripcijski faktori što je i predviđeno analizom
sličnosti s farmakološki poznatim lijekovima iz skupine liganda nuklearnih receptora (NRL
dls) i inhibitora enzima (EI dls) predviđenih računalnim programom Molinspiration (osim za
seletinoida G). Računalnim programom SwissTarget Prediction kao biološke mete ispitivanih
retinoida predviđeni su receptori retinoične kiseline (RAR i RXR), mitogenom-aktivirana
protein kinaza 1, stanični vezujući protein retinoične kiseline 1 i 2 (CRABP), te ornitin
dekarboksilaza za retinoide 1. generacije s vjerojatnošću meta 100% osim za retinol (oko
55%) za kojeg je s 100%-tnom vjerojatnošću predviđen retinol-vezujući plazma protein 1-176
(RBP4), te mitogenom aktivirane kinaze 8-11 i 14 (50%) . Izotretinoin se izdvaja u 1.
generaciji s vjerojatnošću interakcija s RXR receptorima (0%), dok su njegove najvjerojatnije
mete mitogenom aktivirane kinaze 1, 8 i 14 (100%). Prema predviđenim vjerojatnostima
interakcija s metama, retinoidima 1. generacije najsličniji su slijedom fenretinid > beksaroten
> adaroten > pelretin. Mete predviđene za retionide 1. generacije nisu predviđene za nekoliko
retionida 2. do 4. generacije (etretinat, motretinid, tamibaroten, mofaroten i seletinoid G).
Ispitivanje rizika toksičnosti pomoću programa ADMET PredictorTM 8.0 predviđeni su
sljedeći parametri toksičnosti: ADMET rizik 1 (seletinoid G) do 9 (etretinat), CYP rizik od 0
(seletinoid G) do 3 (retinol), TOX rizik od 0 (tamibaroten i temaroten) do 3 (palovaroten) dok
je rizik od mutagenog učinka (TOX MUT Risk 1) predviđen samo za adapalen, tazaroten i
seletinoid G. QSAR studije pokazale su kolinearnost s visokim koeficijentom korelacije (R2 =
0,8067 – 0,9917) za neke molekulske deskriptore (natoma i Mr) s topologijskim indeksima (TI),
a koja nije pronađena s predviđenim sličnostima s lijekom (dls) osim manje značajnih
korelacija za nON s ICM dls i NRL dls (R2 = 0,6989 i 0,6983) kao niti s parametrima
toksičnosti što upućuje na raznolikost strutura i na moguće druge mehanizme djelovanja i
nusdjelovanja unutar skupine ispitivanih retinoida, što se prvenstveno odnosi na seletinoid G.
Abstract (english) The structural features of retinoids and their relationship with biological targets and ADMET
properties were explored using various computer programs. Due to their lipophilicity most
investigated retinoids violate Lipinski ‘Rule 5’ which reflects in reduced oral absorption and
bioavailability. The mechanism of retinoids action involves binding to nuclear receptors that
act as transcription factors which was also confirmed by drug-likeness with nuclear receptor
ligand (NRL dls). In addition to NRL dls, the enzyme inhibitor drug-likeness (EI dls) has
been also computed by Molinspiration software (except for seletinoid G). For 1st generation
of retinoids the following biological targets with high probability (100%) were predicted by
Swiss Target Prediction software, i.e., retinoic acid receptors (RAR and RXR), mitogenactivated
protein kinase 1, cellular retinoic acid binding proteins (CRABP) 1 and 2 and
ornithine decarboxylase. However, these targets were predicted with lower probability (55%)
for retinol in addition to retinol-binding plasma protein 1-176 (RBP4) (100%) and mitogenactivated
kinase 8-11 and 14 (50%). Isotretinoine differs from other retinoids in 1st generation
since zero probability was predicted for its interaction with RXR receptors, whereas its most
likely targets are mitogen-activated kinase 1, 8 and 14 (100%). According to predicted target
probabilities the most similar retinoids from 2nd to 4th generation to those in 1st generation
are in the folowing order fenretinide > bexarotene> adarotene> pelretin, while for etretinate,
motretinide, tamibarotene, mofarotene and seletinoide G were predicted zero probabilities for
typical targets of 1st generation retinoids.
Using ADMET PredictorTM 8.0 the following toxicity risks were predicted: ADMET risk
from 1 (seletinoide G) to 9 (etretinate), CYP risk from 0 (seletinoid G) to 3 (retinol), TOX
risk from 0 (tamibarotene and temarotene) to 3 (palovarotene) while the risk of mutagenic
effect (TOX MUT risk 1) was predicted only for adapalene, tazarotene and seletinoid G.
QSAR studies revealed significant correlations (R2 = 0.8067 - 0.9917) between several
molecular descriptors (natoms and Mr) and topological indices (TI). Insignificant correlations
were found with predicted drug-likeness scores (dls) except for less significant nON with ICM
dls and NRL dls (R2 = 0.6989 and 0.6983) and also with ADMET toxicity parameters. These
results refer to the significant differences in retinoid structures and possibly other mechanisms
of action and side effects in the group of investigated retinoids, especially for seletinoid G.
Keywords
retinoidi
toksičnost
parametri toksičnosti
molekulski deskriptori
topologijski indeksi
Keywords (english)
retinoids
toxicity
toxicity parameters
molecular descriptors
topological indices
Language croatian URN:NBN urn:nbn:hr:163:090306 Study programme Title: Pharmacy Type of resource Text File origin Born digital Access conditions Open access Terms of use Created on 2021-04-21 12:06:22
