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

Нема приказа
Аутори
Oluić, Jelena
Nikolić, Katarina
Vučićević, Jelica
Gagić, Žarko
Filipić, Slavica
Agbaba, Danica
Чланак у часопису (Објављена верзија)
Метаподаци
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Апстракт
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.

Извор:
Combinatorial Chemistry & High Throughput Screening, 2017, 20, 4, 292-303
Издавач:
  • Bentham Science Publ Ltd, Sharjah
Пројекти:
  • Синтеза, квантитативни однос између структуре и дејства, физичко-хемијска карактеризација и анализа фармаколошки активних супстанци (RS-172033)

DOI: 10.2174/1386207320666170427143858

ISSN: 1386-2073

PubMed: 28460621

WoS: 000408462300003

Scopus: 2-s2.0-85028947772
[ Google Scholar ]
7
6
URI
http://farfar.pharmacy.bg.ac.rs/handle/123456789/2818
Колекције
  • Radovi istraživača / Researchers’ publications
Институција
Pharmacy

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