@conference{
author = "Radan, Milica and Antonijević, Mirjana and Đikić, Teodora and Nikolić, Katarina and Agbaba, Danica",
year = "2018",
abstract = "Serotoninski 5‐HT2A receptori su uključeni u mnogobrojne fiziološke i
patofiziološke procese. Strukturno različiti ligandi (agonisti, antagonisti i inverzni
agonisti) dovode do različitih konformacionih promena ovih receptora, izazivajući
brojne biološke odgovore.
Da bi se molekul ponašao kao agonista/antagonista potrebno je da poseduje
različite funkcionalne grupe i specifične interakcije sa određenim aminokiselinama u
vezujućem mestu receptora. Razumevanje i objašnjavanje različitosti u strukturi i
vezivanju za receptor, kod agonista i antagonista, može biti od značaja za racionalni
dizajn novih lekova.
Za razumevanje strukturnih razlika u farmakoforama, kao i kinetici vezivanja i
zmeđu agonista i antagonista korišćeni su ligand‐based i structure‐based pristupi. 3DQSAR
(3D‐quantitative structure activity relationship) studije su izvođene na grupama
od 79 agonista i 90 antagonista. Uporedo su odrađene četiri simulacije molekularne
dinamike: serotoninski 5‐HT2A receptor u kompleksu sa agonistima (serotonin,
lorkaserin) i antagonistima (klozapin, ziprazidon).
Dobijeni statistički i validacioni parametri za modele agonista i antagonista
ukazuju na pouzdanost i dobru predviđajuću moć 3D‐QSAR modela. Najznačajnije
varijable formiranih modela daju nam uvid u najvažnije strukturne razlike između njih.
Rezultati MD simulacije otkrivaju najvažnije razlike u konformacionim promenama
uzrokovane vezivanjem agoniste/antagoniste, kao i interakcije liganada sa ključnim
aminokiselinama, odgovornim za vezivanje. Pomoću trajektorije iz MD simulacije
izvučeni su modeli, 3D strukture 5‐HT2A receptora u njegovom aktivnom (agonistvezujućem)
i inaktivnom (antagonist‐vezujućem) stanju.
Na osnovu ovih in silico rezultata moguće je zaključiti da li je jedinjenje agonista
ili antagonista. Formirani modeli će dalje biti korišćeni za ligand‐based i structure‐based
virtualni skrining i racionalni dizajn novih 5‐HT2A liganada., The serotonin 5‐HT2A receptors have shown a wide range of clinical implications
since they are involved in various physiological and pathophysiological processes.
Structurally diverse ligands (agonists, antagonists, and inverse agonists) can lead to
different biological responses, by provoking different conformational changes of these
receptors.
To behave like an agonist/antagonist the molecule should have a set of
functional groups and specific interactions with certain amino acids in the binding site.
Understanding and explaining dissimilarities in agonist/antagonist structure and
receptor binding would be beneficial for future rational drug design.
To understand structural differences in pharmacophores as well as the binding
kinetics of agonists and antagonists, we have combined ligand‐based and structurebased
approaches. 3D‐quantitative structure‐activity relationship (3D‐QSAR) studies
were performed on a series of 79 agonists and 90 antagonists. Simultaneously, we run
four molecular dynamics (MD) simulations: 5‐HT2A in complex with agonists (serotonin,
lorcaserin), and antagonists (clozapine and ziprasidone).
Obtained statistical and validation parameters for agonists and antagonists
model indicated the reliability and good predictive potential of the 3D‐QSAR models.
The most influential variables of selected models gave us the insight into major
structural dissimilarities between them. Results of MD simulation revealed major
differences in conformational changes caused by agonist/antagonist binding, as well as
ligand interactions with the key amino acids, responsible for them. Additionally, from
MD simulation trajectory, we have extracted 3D structure models of 5‐HT2A in its active
(agonist‐bound) and inactive (antagonist‐bound) state.
Using these finding we will be able to discriminate whether a compound is
agonist or antagonist, in silico. Furthermore, models that we have generated will be
further used for ligand‐based and structure‐based virtual screening and rational drug
design of novel 5‐HT2A ligands.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Kompjuterski dizajn agonista i antognista 5‐HT2A receptora, Combined ligand and structure‐based approach in search of 5‐HT2A receptor agonists and antagonists",
volume = "68",
number = "3",
pages = "389-390",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4878"
}
