3D-QSAR modeling and pharmacophore study of serotonin 5HT-₂A receptors antagonists
3D-QSAR modelovanje i analiza farmakofore antagonista serotoninskih 5-HT2A receptora
Abstract
Creation of a statistically reliable 3D-QSAR (Quantitative Structure Activity Relationships) model enables definition of the structure of the pharmacophore for antagonists of serotonin 5-HT2A receptors and selection of the key molecular determinants for the design of new antagonists. A 3D-QSAR study was applied on a series of 50 antagonists of 5-HT2A receptors. The data set is divided into the training set, composed of 33 compounds, and test set containing 14 molecules. The training set was used to build the 3D-QSAR model, while test set was used for model validation. This 3D-QSAR study was performed by use of the Pentacle 1.07 programs. Obtained statistical and validation parameters for training set (R²= 0.96; Q²=0.75, RMSEE= 0.211); and for test set (R²pred=0.51; RMSEP= 0.558); indicate on reliability and good predictive potential of the 3D-QSAR model. Based on the most influential variables of the selected 3D-QSAR model, the molecular determinants for the antagonistic effect on the ...5-HT2A receptors were selected: hydrogen bond acceptor and hydrogen bond donor at a distance of 10.4A-10.8A (v495: O-N1); carbonyl oxygen and a steric hot spot at a distance of 14.8A-15.2A (v640: N1-TIP); hydrophobic domain and hydrogen bond acceptor at a distance of 3.2A-3.6A (v276: DRY-O); two steric hot spots at a distance of 18.8A-19.2A (v248: TIP-TIP) .
Formiranjem statistički pouzdanog 3D-QSAR (Quantitative Structure Activity Relationships) modela omogućeno je definisanje strukture farmakofore antagonista serotoninskih 5-HT₂A receptora i selekcija ključnih molekulskih determinanti za dizajn novih antagonista serotoninskih 5-HT₂A receptora. 3D-QSAR studija je primenjena na seriji od 50 antagonista serotoninskih 5-HT₂A receptora koji su podeljeni na trening set od 33 molekula i test set od 14 molekula. Trening set je korišćen za formiranje 3D-QSAR modela, dok je test set primenjen za validaciju modela. Za ovu 3D-QSAR studiju je upotrebljen Pentacle 1.07 program. Izračunati validacioni i statistički parametri 3D-QSAR modela (R²=0,96; Q²=0,75; RMSEE= 0,211), kao i parametri eksterne validacije na test setu (R²pred =0,51; RMSEP= 0,558), ukazuju na pouzdanost i dobru moć predviđanja izabranog 3D-QSAR modela. Na osnovu najuticajnijih varijabli izabranog 3D-QSAR modela definisana je struktura farmakofora za antagonističko dejstvo na serotoni...nskim 5-HT₂A receptorima: donor i akceptor vodonične veze na rastojanju od 10,4A-10,8A (v495: O-N1); karbonilni kiseonik i sterni centar na rastojanju od 14,8A-15,2A (v640: N1-TIP); hidrofobni centar i donor vodonične veze na rastojanju od 3,2A- 3,6A (v276: DRY-O); dva sterna centra na rastojanju od 18,8A-19,2A (v248: TIP-TIP).
Keywords:
3D-QSAR / antagonist / 5-HT₂A receptors / pharmacophore / 3D-QSAR / antagonisti / 5-HT₂A receptori / farmakoforaSource:
Arhiv za farmaciju, 2017, 67, 4, 233-247Publisher:
- Savez farmaceutskih udruženja Srbije, Beograd
Funding / projects:
Collections
Institution/Community
PharmacyTY - JOUR AU - Antonijević, Mirjana AU - Nikolić, Katarina AU - Vučićević, Jelica AU - Oljačić, Slavica AU - Agbaba, Danica PY - 2017 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3013 AB - Creation of a statistically reliable 3D-QSAR (Quantitative Structure Activity Relationships) model enables definition of the structure of the pharmacophore for antagonists of serotonin 5-HT2A receptors and selection of the key molecular determinants for the design of new antagonists. A 3D-QSAR study was applied on a series of 50 antagonists of 5-HT2A receptors. The data set is divided into the training set, composed of 33 compounds, and test set containing 14 molecules. The training set was used to build the 3D-QSAR model, while test set was used for model validation. This 3D-QSAR study was performed by use of the Pentacle 1.07 programs. Obtained statistical and validation parameters for training set (R²= 0.96; Q²=0.75, RMSEE= 0.211); and for test set (R²pred=0.51; RMSEP= 0.558); indicate on reliability and good predictive potential of the 3D-QSAR model. Based on the most influential variables of the selected 3D-QSAR model, the molecular determinants for the antagonistic effect on the 5-HT2A receptors were selected: hydrogen bond acceptor and hydrogen bond donor at a distance of 10.4A-10.8A (v495: O-N1); carbonyl oxygen and a steric hot spot at a distance of 14.8A-15.2A (v640: N1-TIP); hydrophobic domain and hydrogen bond acceptor at a distance of 3.2A-3.6A (v276: DRY-O); two steric hot spots at a distance of 18.8A-19.2A (v248: TIP-TIP) . AB - Formiranjem statistički pouzdanog 3D-QSAR (Quantitative Structure Activity Relationships) modela omogućeno je definisanje strukture farmakofore antagonista serotoninskih 5-HT₂A receptora i selekcija ključnih molekulskih determinanti za dizajn novih antagonista serotoninskih 5-HT₂A receptora. 3D-QSAR studija je primenjena na seriji od 50 antagonista serotoninskih 5-HT₂A receptora koji su podeljeni na trening set od 33 molekula i test set od 14 molekula. Trening set je korišćen za formiranje 3D-QSAR modela, dok je test set primenjen za validaciju modela. Za ovu 3D-QSAR studiju je upotrebljen Pentacle 1.07 program. Izračunati validacioni i statistički parametri 3D-QSAR modela (R²=0,96; Q²=0,75; RMSEE= 0,211), kao i parametri eksterne validacije na test setu (R²pred =0,51; RMSEP= 0,558), ukazuju na pouzdanost i dobru moć predviđanja izabranog 3D-QSAR modela. Na osnovu najuticajnijih varijabli izabranog 3D-QSAR modela definisana je struktura farmakofora za antagonističko dejstvo na serotoninskim 5-HT₂A receptorima: donor i akceptor vodonične veze na rastojanju od 10,4A-10,8A (v495: O-N1); karbonilni kiseonik i sterni centar na rastojanju od 14,8A-15,2A (v640: N1-TIP); hidrofobni centar i donor vodonične veze na rastojanju od 3,2A- 3,6A (v276: DRY-O); dva sterna centra na rastojanju od 18,8A-19,2A (v248: TIP-TIP). PB - Savez farmaceutskih udruženja Srbije, Beograd T2 - Arhiv za farmaciju T1 - 3D-QSAR modeling and pharmacophore study of serotonin 5HT-₂A receptors antagonists T1 - 3D-QSAR modelovanje i analiza farmakofore antagonista serotoninskih 5-HT2A receptora VL - 67 IS - 4 SP - 233 EP - 247 DO - 10.5937/arhfarm1704233A ER -
@article{ author = "Antonijević, Mirjana and Nikolić, Katarina and Vučićević, Jelica and Oljačić, Slavica and Agbaba, Danica", year = "2017", abstract = "Creation of a statistically reliable 3D-QSAR (Quantitative Structure Activity Relationships) model enables definition of the structure of the pharmacophore for antagonists of serotonin 5-HT2A receptors and selection of the key molecular determinants for the design of new antagonists. A 3D-QSAR study was applied on a series of 50 antagonists of 5-HT2A receptors. The data set is divided into the training set, composed of 33 compounds, and test set containing 14 molecules. The training set was used to build the 3D-QSAR model, while test set was used for model validation. This 3D-QSAR study was performed by use of the Pentacle 1.07 programs. Obtained statistical and validation parameters for training set (R²= 0.96; Q²=0.75, RMSEE= 0.211); and for test set (R²pred=0.51; RMSEP= 0.558); indicate on reliability and good predictive potential of the 3D-QSAR model. Based on the most influential variables of the selected 3D-QSAR model, the molecular determinants for the antagonistic effect on the 5-HT2A receptors were selected: hydrogen bond acceptor and hydrogen bond donor at a distance of 10.4A-10.8A (v495: O-N1); carbonyl oxygen and a steric hot spot at a distance of 14.8A-15.2A (v640: N1-TIP); hydrophobic domain and hydrogen bond acceptor at a distance of 3.2A-3.6A (v276: DRY-O); two steric hot spots at a distance of 18.8A-19.2A (v248: TIP-TIP) ., Formiranjem statistički pouzdanog 3D-QSAR (Quantitative Structure Activity Relationships) modela omogućeno je definisanje strukture farmakofore antagonista serotoninskih 5-HT₂A receptora i selekcija ključnih molekulskih determinanti za dizajn novih antagonista serotoninskih 5-HT₂A receptora. 3D-QSAR studija je primenjena na seriji od 50 antagonista serotoninskih 5-HT₂A receptora koji su podeljeni na trening set od 33 molekula i test set od 14 molekula. Trening set je korišćen za formiranje 3D-QSAR modela, dok je test set primenjen za validaciju modela. Za ovu 3D-QSAR studiju je upotrebljen Pentacle 1.07 program. Izračunati validacioni i statistički parametri 3D-QSAR modela (R²=0,96; Q²=0,75; RMSEE= 0,211), kao i parametri eksterne validacije na test setu (R²pred =0,51; RMSEP= 0,558), ukazuju na pouzdanost i dobru moć predviđanja izabranog 3D-QSAR modela. Na osnovu najuticajnijih varijabli izabranog 3D-QSAR modela definisana je struktura farmakofora za antagonističko dejstvo na serotoninskim 5-HT₂A receptorima: donor i akceptor vodonične veze na rastojanju od 10,4A-10,8A (v495: O-N1); karbonilni kiseonik i sterni centar na rastojanju od 14,8A-15,2A (v640: N1-TIP); hidrofobni centar i donor vodonične veze na rastojanju od 3,2A- 3,6A (v276: DRY-O); dva sterna centra na rastojanju od 18,8A-19,2A (v248: TIP-TIP).", publisher = "Savez farmaceutskih udruženja Srbije, Beograd", journal = "Arhiv za farmaciju", title = "3D-QSAR modeling and pharmacophore study of serotonin 5HT-₂A receptors antagonists, 3D-QSAR modelovanje i analiza farmakofore antagonista serotoninskih 5-HT2A receptora", volume = "67", number = "4", pages = "233-247", doi = "10.5937/arhfarm1704233A" }
Antonijević, M., Nikolić, K., Vučićević, J., Oljačić, S.,& Agbaba, D.. (2017). 3D-QSAR modeling and pharmacophore study of serotonin 5HT-₂A receptors antagonists. in Arhiv za farmaciju Savez farmaceutskih udruženja Srbije, Beograd., 67(4), 233-247. https://doi.org/10.5937/arhfarm1704233A
Antonijević M, Nikolić K, Vučićević J, Oljačić S, Agbaba D. 3D-QSAR modeling and pharmacophore study of serotonin 5HT-₂A receptors antagonists. in Arhiv za farmaciju. 2017;67(4):233-247. doi:10.5937/arhfarm1704233A .
Antonijević, Mirjana, Nikolić, Katarina, Vučićević, Jelica, Oljačić, Slavica, Agbaba, Danica, "3D-QSAR modeling and pharmacophore study of serotonin 5HT-₂A receptors antagonists" in Arhiv za farmaciju, 67, no. 4 (2017):233-247, https://doi.org/10.5937/arhfarm1704233A . .