New potential inhibitors of mTOR: a computational investigation integrating molecular docking, virtual screening and molecular dynamics simulation

Kist, Roger; Caceres, Rafael Andrade

doi:10.1080/07391102.2016.1262279

Cited by 14 publications

(8 citation statements)

References 51 publications

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“…This site is located in a deep cleft and hydrophobic pocket behind the binding domain. Our control docking is also validated with a similar binding site which has been reported earlier [ 55 ]. It is suggested that the shared macrolide structure between rapamycin and everolimus permits interaction with FKBP5, subsequently to be selective to inhibit mTORC1 over mTORC2 [ 56 ].…”

Section: Resultssupporting

confidence: 55%

In Silico Analyses and Cytotoxicity Study of Asiaticoside and Asiatic Acid from Malaysian Plant as Potential mTOR Inhibitors

et al. 2020

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Natural products remain a popular alternative treatment for many ailments in various countries. This study aimed to screen for potential mammalian target of rapamycin (mTOR) inhibitors from Malaysian natural substance, using the Natural Product Discovery database, and to determine the IC50 of the selected mTOR inhibitors against UMB1949 cell line. The crystallographic structure of the molecular target (mTOR) was obtained from Protein Data Bank, with Protein Data Bank (PDB) ID: 4DRI. Everolimus, an mTOR inhibitor, was used as a standard compound for the comparative analysis. Computational docking approach was performed, using AutoDock Vina (screening) and AutoDock 4.2.6 (analysis). Based on our analysis, asiaticoside and its derivative, asiatic acid, both from Centella asiatica, revealed optimum-binding affinities with mTOR that were comparable to our standard compound. The effect of asiaticoside and asiatic acid on mTOR inhibition was validated with UMB1949 cell line, and their IC50 values were 300 and 60 µM, respectively, compared to everolimus (29.5 µM). Interestingly, this is the first study of asiaticoside and asiatic acid against tuberous sclerosis complex (TSC) disease model by targeting mTOR. These results, coupled with our in silico findings, should prompt further studies, to clarify the mode of action, safety, and efficacy of these compounds as mTOR inhibitors.

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Section: Resultssupporting

confidence: 55%

In Silico Analyses and Cytotoxicity Study of Asiaticoside and Asiatic Acid from Malaysian Plant as Potential mTOR Inhibitors

et al. 2020

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“…As shown in Figure 1 , the docked conformation predicted for rapamycin (in violet) is spatially close to the crystallographic structure pose (in yellow) with an optimal RMSD value of 1.44 Å. In addition, as shown in Table 1 , the best binding energy calculated for rapamycin (−8.6 kcal·mol) was in good agreement with the literature data (−8.4 kcal·mol) [ 26 ]. These findings indicate a high-level of the feasibility in our protein-ligand docking procedure, which was able to reproduce the binding pose of the cocrystallized ligand deposited in the PDB ID: 4DRI.…”

Section: Resultssupporting

confidence: 81%

Carvacrol: An In Silico Approach of a Candidate Drug on HER2, PI3Kα, mTOR, hER‐α, PR, and EGFR Receptors in the Breast Cancer

Herrera-Calderon

Yepes-Pérez

Quintero‐Saumeth

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Carvacrol is a phenol monoterpene found in aromatic plants specially in Lamiaceae family, which has been evaluated in an experimental model of breast cancer. However, any proposed mechanism based on its antitumor effect has not been reported. In our previous study, carvacrol showed a protective effect on 7,12-dimethylbenz[α]anthracene- (DMBA-) induced breast cancer in female rats. The main objective in this research was to evaluate by using in silico study the carvacrol on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR receptors involved in breast cancer progression by docking analysis, molecular dynamic, and drug-likeness evaluation. A multilevel computational study to evaluate the antitumor potential of carvacrol focusing on the main targets involved in the breast cancer was carried out. The in silico study starts with protein-ligand docking of carvacrol followed by ligand pathway calculations, molecular dynamic simulations, and molecular mechanics energies combined with the Poisson–Boltzmann (MM/PBSA) calculation of the free energy of binding for carvacrol. As result, the in silico study led to the identification of carvacrol with strong binding affinity on mTOR receptor. Additionally, in silico drug-likeness index for carvacrol showed a good predicted therapeutic profile of druggability. Our findings suggest that mTOR signaling pathway could be responsible for its preventive effect in the breast cancer.

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“…An important signaling pathway called PI3K/Akt/mTOR pathway is believed to be the most frequently dysregulated pathway in various cancers [Samuels et al, 2004;Engelman et al, 2006;Liu et al, 2009] and therefore, the key proteins of this pathway is often targeted in multitude of cancer types [Morgensztern and McLeod, 2005;Shuttleworth et al, 2011;Jamal et al, 2014;Polivka and Janku, 2014;Porta et al, 2014;Rehan et al, 2014;Rehan, 2015]. One of such key proteins of this pathway is mammalian target of rapamycin (mTOR), which is widely exploited as a drug target for anti-cancer therapy [Helena et al, 2012;Kist and Caceres, 2016;Wang et al, 2016].…”

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confidence: 99%

An Anti‐Cancer Drug Candidate OSI‐027 and its Analog as Inhibitors of mTOR: Computational Insights Into the Inhibitory Mechanisms

Rehan

2017

J of Cellular Biochemistry

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The mammalian target of rapamycin (mTOR) is a serine-threonine kinase, which regulates cellular metabolism and growth, and is a validated therapeutic target in various cancers. Recently, OSI-027, a selective ATP competitive inhibitor of mTOR, has been developed. The OSI-027 is an orally bioavailable compound whose anti-cancer activities were observed in various cancer cell lines and tumor xenograft models. The current study is the first attempt to explore the binding mode and the molecular-interactions of OSI-027 with mTOR using molecular docking and (un)binding simulation approaches. The study identified various interacting residues and their extent of involvement in binding was emphasized using different methods. The (un)binding simulation analyses provided snapshots of various phases in OSI-027 binding and identified residues important for binding but away from the catalytic site. Further, to explore a better binder for mTOR among OSI-027 analogs, the virtual screening led to propose an OSI-027 analog with CID: 73294902 as a better inhibitor than the OSI-027 and the native ligand PI-103. The binding mode of the proposed compound is compared with those of OSI-027 and other native inhibitors. The comparison of (un)binding simulation phases of proposed compound with that of OSI-027 revealed that both, bound to the same catalytic site, follow different (un)binding path. Thus, the current study presents computational insights into the OSI-027 mediated inhibition of mTOR kinase and proposed an OSI-027 analog as better mTOR inhibitor, and thus, a good drug for further research in experimental laboratories. J. Cell. Biochem. 118: 4558-4567, 2017. © 2017 Wiley Periodicals, Inc.

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New potential inhibitors of mTOR: a computational investigation integrating molecular docking, virtual screening and molecular dynamics simulation

Cited by 14 publications

References 51 publications

In Silico Analyses and Cytotoxicity Study of Asiaticoside and Asiatic Acid from Malaysian Plant as Potential mTOR Inhibitors

In Silico Analyses and Cytotoxicity Study of Asiaticoside and Asiatic Acid from Malaysian Plant as Potential mTOR Inhibitors

Carvacrol: An In Silico Approach of a Candidate Drug on HER2, PI3Kα, mTOR, hER‐α, PR, and EGFR Receptors in the Breast Cancer

An Anti‐Cancer Drug Candidate OSI‐027 and its Analog as Inhibitors of mTOR: Computational Insights Into the Inhibitory Mechanisms

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