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3D-QSAR, Virtual Screening, Docking and Design of Dual PI3K/mTOR Inhibitors with Enhanced Antiproliferative Activity

Nema prikaza
Autori
Oluić, Jelena
Nikolić, Katarina
Vučićević, Jelica
Gagić, Žarko
Filipić, Slavica
Agbaba, Danica
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentu
Apstrakt
Aim and Objective: Altered activity of PI3K/mTOR signaling pathway is one of the most common aberrations found in various forms of neoplastic lesions. Dual inhibition of PI3K and mTOR represents a reasonably attractive concept in potential cancer treatment. The main aim of this work was to design novel PI3K/mTOR inhibitors with enhanced antiproliferative activity. Materials and Methods: 3D-QSAR pharmacophore modeling studies were performed on two groups comprised of 37 and 48 dual PI3K/mTOR inhibitors. Obtained 3D-pharmacophores were used in design of new dual PI3K/mTOR inhibitors. Based on the in silico ADMET data, structure-based virtual screening and docking studies, the most promising novel candidates were selected. Results: Four reliable PLS models with good statistical parameters (q(2) (=) 0.72, r(pred)(2) = 0.93; q(2) = 0.81, r(pred)(2) = 0.88 for 3D-QSAR (mTOR) models and q(2) = 0.79, r(pred)(2) = 0.93; q(2) = 0.79, r(pred)(2) = 0.94 for 3D-QSAR (PI3K) models) were obtained and... new highly selective and potent dual PI3K/mTOR inhibitors were designed. Further in silico ADMET profiling of the designed compounds selected the most promising novel PI3K/mTOR inhibitors as drug candidates. Results of the 3D-QSAR studies were confirmed by structure-based virtual screening protocol that identified selected designed compounds as a best fit for PI3K and mTOR receptors. Molecular docking studies on PI3K and mTOR crystal structures revealed the key active site residues involved in binding of PI3K/mTOR ligands. Conclusion: After combining the results of 3D-QSAR, ADMET profiling, virtual screening and docking, compounds 56-57 and 56-62 were chosen as the most promising new dual PI3K/mTOR inhibitors.

Izvor:
Combinatorial Chemistry & High Throughput Screening, 2017, 20, 4, 292-303
Izdavač:
  • Bentham Science Publ Ltd, Sharjah
Finansiranje / projekti:
  • Sinteza, kvantitativni odnos između strukture i dejstva, fizičko-hemijska karakterizacija i analiza farmakološki aktivnih supstanci (RS-172033)

DOI: 10.2174/1386207320666170427143858

ISSN: 1386-2073

PubMed: 28460621

WoS: 000408462300003

Scopus: 2-s2.0-85028947772
[ Google Scholar ]
7
7
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/2818
Kolekcije
  • Radovi istraživača / Researchers’ publications
Institucija/grupa
Pharmacy
TY  - JOUR
AU  - Oluić, Jelena
AU  - Nikolić, Katarina
AU  - Vučićević, Jelica
AU  - Gagić, Žarko
AU  - Filipić, Slavica
AU  - Agbaba, Danica
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2818
AB  - Aim and Objective: Altered activity of PI3K/mTOR signaling pathway is one of the most common aberrations found in various forms of neoplastic lesions. Dual inhibition of PI3K and mTOR represents a reasonably attractive concept in potential cancer treatment. The main aim of this work was to design novel PI3K/mTOR inhibitors with enhanced antiproliferative activity. Materials and Methods: 3D-QSAR pharmacophore modeling studies were performed on two groups comprised of 37 and 48 dual PI3K/mTOR inhibitors. Obtained 3D-pharmacophores were used in design of new dual PI3K/mTOR inhibitors. Based on the in silico ADMET data, structure-based virtual screening and docking studies, the most promising novel candidates were selected. Results: Four reliable PLS models with good statistical parameters (q(2) (=) 0.72, r(pred)(2) = 0.93; q(2) = 0.81, r(pred)(2) = 0.88 for 3D-QSAR (mTOR) models and q(2) = 0.79, r(pred)(2) = 0.93; q(2) = 0.79, r(pred)(2) = 0.94 for 3D-QSAR (PI3K) models) were obtained and new highly selective and potent dual PI3K/mTOR inhibitors were designed. Further in silico ADMET profiling of the designed compounds selected the most promising novel PI3K/mTOR inhibitors as drug candidates. Results of the 3D-QSAR studies were confirmed by structure-based virtual screening protocol that identified selected designed compounds as a best fit for PI3K and mTOR receptors. Molecular docking studies on PI3K and mTOR crystal structures revealed the key active site residues involved in binding of PI3K/mTOR ligands. Conclusion: After combining the results of 3D-QSAR, ADMET profiling, virtual screening and docking, compounds 56-57 and 56-62 were chosen as the most promising new dual PI3K/mTOR inhibitors.
PB  - Bentham Science Publ Ltd, Sharjah
T2  - Combinatorial Chemistry & High Throughput Screening
T1  - 3D-QSAR, Virtual Screening, Docking and Design of Dual PI3K/mTOR Inhibitors with Enhanced Antiproliferative Activity
VL  - 20
IS  - 4
SP  - 292
EP  - 303
DO  - 10.2174/1386207320666170427143858
ER  - 
@article{
author = "Oluić, Jelena and Nikolić, Katarina and Vučićević, Jelica and Gagić, Žarko and Filipić, Slavica and Agbaba, Danica",
year = "2017",
abstract = "Aim and Objective: Altered activity of PI3K/mTOR signaling pathway is one of the most common aberrations found in various forms of neoplastic lesions. Dual inhibition of PI3K and mTOR represents a reasonably attractive concept in potential cancer treatment. The main aim of this work was to design novel PI3K/mTOR inhibitors with enhanced antiproliferative activity. Materials and Methods: 3D-QSAR pharmacophore modeling studies were performed on two groups comprised of 37 and 48 dual PI3K/mTOR inhibitors. Obtained 3D-pharmacophores were used in design of new dual PI3K/mTOR inhibitors. Based on the in silico ADMET data, structure-based virtual screening and docking studies, the most promising novel candidates were selected. Results: Four reliable PLS models with good statistical parameters (q(2) (=) 0.72, r(pred)(2) = 0.93; q(2) = 0.81, r(pred)(2) = 0.88 for 3D-QSAR (mTOR) models and q(2) = 0.79, r(pred)(2) = 0.93; q(2) = 0.79, r(pred)(2) = 0.94 for 3D-QSAR (PI3K) models) were obtained and new highly selective and potent dual PI3K/mTOR inhibitors were designed. Further in silico ADMET profiling of the designed compounds selected the most promising novel PI3K/mTOR inhibitors as drug candidates. Results of the 3D-QSAR studies were confirmed by structure-based virtual screening protocol that identified selected designed compounds as a best fit for PI3K and mTOR receptors. Molecular docking studies on PI3K and mTOR crystal structures revealed the key active site residues involved in binding of PI3K/mTOR ligands. Conclusion: After combining the results of 3D-QSAR, ADMET profiling, virtual screening and docking, compounds 56-57 and 56-62 were chosen as the most promising new dual PI3K/mTOR inhibitors.",
publisher = "Bentham Science Publ Ltd, Sharjah",
journal = "Combinatorial Chemistry & High Throughput Screening",
title = "3D-QSAR, Virtual Screening, Docking and Design of Dual PI3K/mTOR Inhibitors with Enhanced Antiproliferative Activity",
volume = "20",
number = "4",
pages = "292-303",
doi = "10.2174/1386207320666170427143858"
}
Oluić, J., Nikolić, K., Vučićević, J., Gagić, Ž., Filipić, S.,& Agbaba, D.. (2017). 3D-QSAR, Virtual Screening, Docking and Design of Dual PI3K/mTOR Inhibitors with Enhanced Antiproliferative Activity. in Combinatorial Chemistry & High Throughput Screening
Bentham Science Publ Ltd, Sharjah., 20(4), 292-303.
https://doi.org/10.2174/1386207320666170427143858
Oluić J, Nikolić K, Vučićević J, Gagić Ž, Filipić S, Agbaba D. 3D-QSAR, Virtual Screening, Docking and Design of Dual PI3K/mTOR Inhibitors with Enhanced Antiproliferative Activity. in Combinatorial Chemistry & High Throughput Screening. 2017;20(4):292-303.
doi:10.2174/1386207320666170427143858 .
Oluić, Jelena, Nikolić, Katarina, Vučićević, Jelica, Gagić, Žarko, Filipić, Slavica, Agbaba, Danica, "3D-QSAR, Virtual Screening, Docking and Design of Dual PI3K/mTOR Inhibitors with Enhanced Antiproliferative Activity" in Combinatorial Chemistry & High Throughput Screening, 20, no. 4 (2017):292-303,
https://doi.org/10.2174/1386207320666170427143858 . .

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