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dc.creatorOluić, Jelena
dc.creatorNikolić, Katarina
dc.creatorVučićević, Jelica
dc.creatorGagić, Žarko
dc.creatorFilipić, Slavica
dc.creatorAgbaba, Danica
dc.date.accessioned2019-09-02T11:57:57Z
dc.date.available2019-09-02T11:57:57Z
dc.date.issued2017
dc.identifier.issn1386-2073
dc.identifier.urihttp://farfar.pharmacy.bg.ac.rs/handle/123456789/2818
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.rightsrestrictedAccess
dc.sourceCombinatorial Chemistry & High Throughput Screening
dc.title3D-QSAR, Virtual Screening, Docking and Design of Dual PI3K/mTOR Inhibitors with Enhanced Antiproliferative Activityen
dc.typearticle
dc.rights.licenseARR
dcterms.abstractAгбаба, Даница; Филипић, Славица; Николић, Катарина; Олуић, Јелена; Вучићевић, Јелица; Гагић, Жарко;
dc.citation.volume20
dc.citation.issue4
dc.citation.spage292
dc.citation.epage303
dc.citation.other20(4): 292-303
dc.citation.rankM23
dc.identifier.wos000408462300003
dc.identifier.doi10.2174/1386207320666170427143858
dc.identifier.pmid28460621
dc.identifier.scopus2-s2.0-85028947772
dc.identifier.rcubconv_3929
dc.type.versionpublishedVersion


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