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 (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.Keywords: PI3K/mTOR kinases, dual inhibitors, 3D-QSAR, virtual screening, molecular docking.
Combinatorial Chemistry & High Throughput Screening
Title:3D-QSAR, Virtual Screening, Docking and Design of Dual PI3K/mTOR Inhibitors with Enhanced Antiproliferative Activity
Volume: 20 Issue: 4
Author(s): Jelena Oluić, Katarina Nikolic, Jelica Vucicevic, Zarko Gagic*, Slavica Filipic and Danica Agbaba
Affiliation:
- Department of Pharmacy, Faculty of Medicine, Save Mrkalja 14, University of Banja Luka, 78000 Banja Luka,Bosnia and Herzegovina
Keywords: PI3K/mTOR kinases, dual inhibitors, 3D-QSAR, virtual screening, molecular docking.
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 (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.Export Options
About this article
Cite this article as:
Oluić Jelena , Nikolic Katarina, Vucicevic Jelica, Gagic Zarko *, Filipic Slavica and Agbaba Danica, 3D-QSAR, Virtual Screening, Docking and Design of Dual PI3K/mTOR Inhibitors with Enhanced Antiproliferative Activity, Combinatorial Chemistry & High Throughput Screening 2017; 20 (4) . https://dx.doi.org/10.2174/1386207320666170427143858
DOI https://dx.doi.org/10.2174/1386207320666170427143858 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
![](/images/wayfinder.jpg)
- Author Guidelines
- Bentham Author Support Services (BASS)
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers