Combinatorial Chemistry & High Throughput Screening

Rathnam Chaguturu 
iDDPartners, 3 Edith Court
Princeton Junction
NJ 08550
USA

Back

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

Author(s): Jelena Oluić, Katarina Nikolic, Jelica Vucicevic, Zarko Gagic, Slavica Filipic, Danica Agbaba.

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.

Order Reprints Order Eprints Rights & PermissionsPrintExport

Article Details

VOLUME: 20
ISSUE: 4
Year: 2017
Page: [292 - 303]
Pages: 12
DOI: 10.2174/1386207320666170427143858
Price: $58