3D-QSAR, Virtual Screening, Docking and Design of Dual PI3K/mTOR Inhibitors with Enhanced Antiproliferative Activity.
Comb Chem High Throughput Screen
; 20(4): 292-303, 2017 Aug 10.
Article
em En
| MEDLINE
| ID: mdl-28460621
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 ANDMETHODS:
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 (q2 = 0.72, r2 pred = 0.93; q2 = 0.81, r2 pred= 0.88 for 3D-QSAR (mTOR) models and q2 = 0.79, r2pred = 0.93; q2 = 0.79, r2 pred = 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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
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Inibidores de Proteínas Quinases
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Serina-Treonina Quinases TOR
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Simulação de Acoplamento Molecular
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Inibidores de Fosfoinositídeo-3 Quinase
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article