Show simple item record

dc.creatorOluić, Jelena
dc.creatorNikolić, Katarina
dc.creatorVučićević, Jelica
dc.creatorGagić, Žarko
dc.creatorFilipić, Slavica
dc.creatorAgbaba, Danica
dc.description.abstractAim 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.en
dc.publisherBentham Science Publ Ltd, Sharjah
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172033/RS//
dc.sourceCombinatorial Chemistry & High Throughput Screening
dc.title3D-QSAR, Virtual Screening, Docking and Design of Dual PI3K/mTOR Inhibitors with Enhanced Antiproliferative Activityen
dcterms.abstractAгбаба, Даница; Филипић, Славица; Николић, Катарина; Олуић, Јелена; Вучићевић, Јелица; Гагић, Жарко;
dc.citation.other20(4): 292-303

Files in this item


There are no files associated with this item.

This item appears in the following Collection(s)

Show simple item record