In silico development of new PET radiopharmaceuticals from mTOR inhibitors

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase portraying a quintessential role in cellular proliferation and survival. Aberrations in the mTOR signaling pathway have been reported in numerous cancers including thyroid, lung, gastric and ovarian cancer, thus making it a therapeutic target. To attain this objective, an in silico investigation was designed, employing a pharmacophore modeling approach. A structure-based pharmacophore (SBP) model exploiting the key features of a selective mTOR inhibitor, Torkinib directed at the ATP-binding pocket was generated. A Marine Natural Products (MNP) library was screened using SBP model as a query. The retrieved compounds after consequent drug-likeness filtration were subjected to molecular docking with mTOR, thus revealing four MNPs with better scores than Torkinib. Successive refinement via molecular dynamics simulations demonstrated that the hits formed crucial interactions with key residues of the pocket. Furthermore, the four identified hits exhibited good binding free energy scores through MM-PBSA calculations and the subsequent in silico toxicity assessments displayed three hits deemed essentially non-carcinogenic and non-mutagenic. The hits presented in this investigation could act as potent ATP-competitive mTOR inhibitors, representing a platform for the future discovery of drugs from marine natural origin.

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Design, Synthesis and SAR in 2,4,7-Trisubstituted Pyrido[3.2-d]Pyrimidine Series as Novel PI3K/mTOR Inhibitors

Molecules ◽

10.3390/molecules26175349 ◽

2021 ◽

Vol 26 (17) ◽

pp. 5349

Author(s):

Frédéric Buron ◽

Nuno Rodrigues ◽

Thibault Saurat ◽

Marie Aude Hiebel ◽

Stéphane Bourg ◽

...

Keyword(s):

Cell Lines ◽

In Silico ◽

Mtor Inhibitors ◽

Pi3k Pathway ◽

Chemical Diversity ◽

Design Synthesis ◽

In Silico Docking ◽

Pyrimidine Series ◽

Molecular Determinants ◽

Ic50 Values

This work describes the synthesis, enzymatic activities on PI3K and mTOR, in silico docking and cellular activities of various uncommon 2,4,7 trisubstituted pyrido[3.2-d]pyrimidines. The series synthesized offers a chemical diversity in C-7 whereas C-2 (3-hydroxyphenyl) and C-4 groups (morpholine) remain unchanged, in order to provide a better understanding of the molecular determinants of PI3K selectivity or dual activity on PI3K and mTOR. Some C-7 substituents were shown to improve the efficiency on kinases compared to the 2,4-di-substituted pyrimidopyrimidine derivatives used as references. Six novel derivatives possess IC50 values on PI3Kα between 3 and 10 nM. The compounds with the best efficiencies on PI3K and mTOR induced micromolar cytotoxicity on cancer cell lines possessing an overactivated PI3K pathway.

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

Molecules ◽

10.3390/molecules25173991 ◽

2020 ◽

Vol 25 (17) ◽

pp. 3991

Author(s):

Ninie Nadia Zulkipli ◽

Rahimah Zakaria ◽

Idris Long ◽

Siti Fadilah Abdullah ◽

Erma Fatiha Muhammad ◽

...

Keyword(s):

Cell Line ◽

Protein Data Bank ◽

In Silico ◽

Mtor Inhibitors ◽

Data Bank ◽

Crystallographic Structure ◽

Asiatic Acid ◽

Mtor Inhibition ◽

Computational Docking ◽

Standard Compound

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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Support for phosphoinositol 3 kinase and mTOR inhibitors as treatment for lupus using in-silico drug-repurposing analysis

Arthritis Research & Therapy ◽

10.1186/s13075-017-1263-7 ◽

2017 ◽

Vol 19 (1) ◽

Cited By ~ 9

Author(s):

Daniel Toro-Domínguez ◽

Pedro Carmona-Sáez ◽

Marta E. Alarcón-Riquelme

Keyword(s):

In Silico ◽

Drug Repurposing ◽

Mtor Inhibitors

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In silico Analysis and Molecular Docking Studies of Novel 4-Amino-3- (Isoquinolin-4-yl)-1H-Pyrazolo[3,4-d]Pyrimidine Derivatives as Dual PI3-K/mTOR Inhibitors

Current Drug Discovery Technologies ◽

10.2174/1568009618666181102144934 ◽

2019 ◽

Vol 16 (3) ◽

pp. 297-306

Author(s):

Ishan I. Panchal ◽

Sandip N. Badeliya ◽

Rakesh Patel ◽

Ashish Patel ◽

Animesh Devaligar

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

In Silico ◽

Growth Control ◽

In Silico Analysis ◽

Software Tool ◽

Mtor Inhibitors ◽

Docking Studies ◽

Tissue Growth ◽

Nucleotide Synthesis

Background: mTORC1/ PI3K control multiple anabolic pathways, including protein synthesis, ribosome production, lipogenesis, and nucleotide synthesis, are all important for cell and tissue growth. Sapanisertib and Dactolisib inhibit PI3K/AKT/mTOR pathway, an important signaling pathway for many cellular functions such as growth control, metabolism and translation initiation. Methods: Dactolisib contains quinolin-3-yl-2,3-dihydroimidazo[4,5-c]quinolin scaffold and Sapanisertib contains benzo[d]oxazol-5-yl-1-ethyl-1H-pyrazolo[3,4-d]pyrimidinnucleous. From the reference to both of drug novel series of 4-Amino-3-(isoquinolin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin was developed by molecular docking. In sillico analysis was done with SWISSADME online tools. Results: Among all the designed derivatives, compounds 6(-10.6 kcal/mol) , 12( -10.7 kcal/mol), 14( -10.2 kcal/mol), and 16(-10.2 kcal/mol) have a good binding affinity than others. Biological activity was predicted by Molinspirationonline software tool showing that all compounds are active on G- protein coupled receptor. In silico toxicity profile of designed compounds was performed using the SWISSADME program, indicating that all the compounds follow the Lipinski rule of five and do not penetrate Blood brain barrier. Conclusion: Series of pyrazolo[3,4-d]pyrimidin derivatives gives good binding affinity with pan- PI3-Kinese/Mtor inhibitors. The present study provided a better understanding of the molecular modeling requisite for maintaining and/or improving PI3K/mTOR inhibitors.

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