scholarly journals New Mammalian Target of Rapamycin (mTOR) Modulators Derived from Natural Product Databases and Marine Extracts by Using Molecular Docking Techniques

Marine Drugs ◽  
2018 ◽  
Vol 16 (10) ◽  
pp. 385 ◽  
Author(s):  
Verónica Ruiz-Torres ◽  
Maria Losada-Echeberría ◽  
Maria Herranz-López ◽  
Enrique Barrajón-Catalán ◽  
Vicente Galiano ◽  
...  
Keyword(s):  
Natural Products ◽  
Molecular Docking ◽  
Side Effects ◽  
Inhibitory Activity ◽  
Mammalian Target Of Rapamycin ◽  
Therapeutic Use ◽  
Cellular Growth ◽  
Target Of Rapamycin ◽  
Computational Techniques ◽  
Chemical Derivatives

Mammalian target of rapamycin (mTOR) is a PI3K-related serine/threonine protein kinase that functions as a master regulator of cellular growth and metabolism, in response to nutrient and hormonal stimuli. mTOR functions in two distinct complexes—mTORC1 is sensitive to rapamycin, while, mTORC2 is insensitive to this drug. Deregulation of mTOR’s enzymatic activity has roles in cancer, obesity, and aging. Rapamycin and its chemical derivatives are the only drugs that inhibit the hyperactivity of mTOR, but numerous side effects have been described due to its therapeutic use. The purpose of this study was to identify new compounds of natural origin that can lead to drugs with fewer side effects. We have used computational techniques (molecular docking and calculated ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) parameters) that have enabled the selection of candidate compounds, derived from marine natural products, SuperNatural II, and ZINC natural products, for inhibitors targeting, both, the ATP and the rapamycin binding sites of mTOR. We have shown experimental evidence of the inhibitory activity of eleven selected compounds against mTOR. We have also discovered the inhibitory activity of a new marine extract against this enzyme. The results have been discussed concerning the necessity to identify new molecules for therapeutic use, especially against aging, and with fewer side effects.

scholarly journals The mammalian target of rapamycin (mTOR) kinase mediates haloperidol-induced cataleptic behavior

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Uri Nimrod Ramírez-Jarquín ◽  
Neelam Shahani ◽  
William Pryor ◽  
Alessandro Usiello ◽  
Srinivasa Subramaniam
Keyword(s):  
Side Effects ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Typical Antipsychotic ◽  
Dependent Manner ◽  
Serine Threonine Kinase ◽  
Therapeutic Benefits ◽  
Dopamine 2 Receptor ◽  
Pharmacological Method ◽  
Extrapyramidal Motor

Abstract The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy, and pS6K (T389) and pS6 (S235/236) signaling upregulation, in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side effects of haloperidol in psychiatric illness.

The kinase triad, AMPK, mTORC1 and ULK1, maintains energy and nutrient homoeostasis

2013 ◽  
Vol 41 (4) ◽  
pp. 939-943 ◽  
Author(s):  
Elaine A. Dunlop ◽  
Andrew R. Tee
Keyword(s):  
Amino Acid ◽  
Cell Growth ◽  
Protein Kinases ◽  
Mammalian Target Of Rapamycin ◽  
Nutrient Status ◽  
Protein Translation ◽  
Cellular Growth ◽  
Target Of Rapamycin ◽  
Amp Activated Protein Kinase ◽  
Rate Limiting

In order for cells to divide in a proficient manner, they must first double their biomass, which is considered to be the main rate-limiting phase of cell proliferation. Cell growth requires an abundance of energy and biosynthetic precursors such as lipids and amino acids. Consequently, the energy and nutrient status of the cell is acutely monitored and carefully maintained. mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] is often considered to be the master regulator of cell growth that enhances cellular biomass through up-regulation of protein translation. In order for cells to control cellular homoeostasis during growth, there is close signalling interplay between mTORC1 and two other protein kinases, AMPK (AMP-activated protein kinase) and ULK1 (Unc-51-like kinase 1). This kinase triad collectively senses the energy and nutrient status of the cell and appropriately dictates whether the cell will actively favour energy- and amino-acid-consuming anabolic processes such as cellular growth, or energy- and amino-acid-generating catabolic processes such as autophagy. The present review discusses important feedback mechanisms between these three homoeostatic protein kinases that orchestrate cell growth and autophagy, with a particular focus on the mTORC1 component raptor (regulatory associated protein of mammalian target of rapamycin), as well as the autophagy-initiating kinase ULK1.

scholarly journals The Mammalian Target of Rapamycin (mTOR) Kinase Mediates Haloperidol-Induced Cataleptic Behavior

2020 ◽  
Author(s):  
Uri Nimrod Ramírez-Jarquín ◽  
Neelam Shahani ◽  
William Pryor ◽  
Alessandro Usiello ◽  
Srinivasa Subramaniam
Keyword(s):  
Side Effects ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Typical Antipsychotic ◽  
Dependent Manner ◽  
Serine Threonine Kinase ◽  
Therapeutic Benefits ◽  
Dopamine 2 Receptor ◽  
Pharmacological Method ◽  
Extrapyramidal Motor

ABSTRACTThe mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side-effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side-effects of haloperidol in psychiatric illness.

Everolimus-induced near-resolution of giant cardiac rhabdomyomas and large renal angiomyolipoma in a newborn with tuberous sclerosis complex

2016 ◽  
Vol 26 (5) ◽  
pp. 1025-1028 ◽  
Author(s):  
Massimo Colaneri ◽  
Andrea Quarti ◽  
Marco Pozzi
Keyword(s):  
Side Effects ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Renal Angiomyolipoma ◽  
Cardiac Rhabdomyoma

AbstractWe report a case of a newborn, affected by tuberous sclerosis complex, with a prenatally diagnosed giant cardiac rhabdomyoma associated with a large renal angiomyolipoma presenting as a duct-depending lesion not treatable by surgery. After receiving everolimus, a mammalian target of rapamycin inhibitor, we observed a rapid, significant, and durable reduction of both lesions without remarkable side effects.

scholarly journals mTOR Links Tumor Immunity and Bone Metabolism: What are the Clinical Implications?

2019 ◽  
Vol 20 (23) ◽  
pp. 5841 ◽  
Author(s):  
Azzurra Irelli ◽  
Maria Maddalena Sirufo ◽  
Teresa Scipioni ◽  
Francesca De Pietro ◽  
Amedeo Pancotti ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Tumor Immunity ◽  
Transforming Growth Factor ◽  
Cytotoxic T Lymphocyte ◽  
Mammalian Target Of Rapamycin ◽  
Membrane Receptors ◽  
Cellular Growth ◽  
Target Of Rapamycin ◽  
Downstream Signaling ◽  
Phosphoinositide 3 Kinase

Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) plays a crucial role in the control of cellular growth, proliferation, survival, metabolism, angiogenesis, transcription, and translation. In most human cancers, alterations to this pathway are common and cause activation of other downstream signaling pathways linked with oncogenesis. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both tumor immunity and angiogenesis. Inflammation is a hallmark of cancer, playing a central role in the tumor dynamics, and immune cells can exert antitumor functions or promote the growth of cancer cells. In this context, mTOR may regulate the activity of macrophages and T cells by regulating the expression of cytokines/chemokines, such as interleukin (IL)-10 and transforming growth factor (TGF-β), and/or membrane receptors, such as cytotoxic T-Lymphocyte protein 4 (CTLA-4) and Programmed Death 1 (PD-1). Furthermore, inhibitors of mammalian target of rapamycin are demonstrated to actively modulate osteoclastogenesis, exert antiapoptotic and pro-differentiative activities in osteoclasts, and reduce the number of lytic bone metastases, increasing bone mass in tumor-bearing mice. With regard to the many actions in which mTOR is involved, the aim of this review is to describe its role in the immune system and bone metabolism in an attempt to identify the best strategy for therapeutic opportunities in the metastatic phase of solid tumors.

scholarly journals Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Chuanjun Zhuo ◽  
Yong Xu ◽  
Weihong Hou ◽  
Jiayue Chen ◽  
Qianchen Li ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Weight Gain ◽  
Side Effects ◽  
Antipsychotic Drugs ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Glucose And Lipid Metabolism ◽  
Pathway Activation ◽  
Extrapyramidal Motor

AbstractAntipsychotic pharmacotherapy has been widely recommended as the standard of care for the treatment of acute schizophrenia and psychotic symptoms of other psychiatric disorders. However, there are growing concerns regarding antipsychotic-induced side effects, including weight gain, metabolic syndrome (MetS), and extrapyramidal motor disorders, which not only decrease patient compliance, but also predispose to diabetes and cardiovascular diseases. To date, most studies and reviews on the mechanisms of antipsychotic-induced metabolic side effects have focused on central nervous system mediation of appetite and food intake. However, disturbance in glucose and lipid metabolism, and hepatic steatosis induced by antipsychotic drugs might precede weight gain and MetS. Recent studies have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical regulatory role in the pathophysiology of antipsychotic drug-induced disorders of hepatic glucose and lipid metabolism. Furthermore, antipsychotic drugs promote striatal mTOR pathway activation that contributes to extrapyramidal motor side effects. Although recent findings have advanced the understanding of the role of the mTOR pathway in antipsychotic-induced side effects, few reviews have been conducted on this emerging topic. In this review, we synthesize key findings by focusing on the roles of the hepatic and striatal mTOR pathways in the pathogenesis of metabolic and extrapyramidal side effects, respectively. We further discuss the potential therapeutic benefits of normalizing excessive mTOR pathway activation with mTOR specific inhibitors. A deeper understanding of pathogenesis may inform future intervention strategies using the pharmacological or genetic inhibitors of mTOR to prevent and manage antipsychotic-induced side effects.

Molecular Docking Approaches to Suggest the Anti-Mycobacterial Targets of Natural Products

2020 ◽  
Author(s):  
Rafael Baptista ◽  
Sumana Bhowmick ◽  
Shen Jianying ◽  
Luis Mur
Keyword(s):  
Natural Products ◽  
Molecular Docking ◽  
Free Energies ◽  
Antibiotic Resistant ◽  
Drug Lead ◽  
Bisbenzylisoquinoline Alkaloids ◽  
Docking Approach ◽  
Global Threat ◽  
Physicochemical And Structural Properties

Tuberculosis (TB) is a major global threat mostly due to the development of antibiotic resistant forms of Mycobacterium tuberculosis, the causal agent of the disease. Driven by the pressing need for new anti-mycobacterial agents, several natural products (NPs) have been shown to have in vitro activities against M. tuberculosis. The utility of any NP as a drug lead is augmented when the anti-mycobacterial target(s) is unknown. To suggest these, we used a molecular docking approach to predict the interactions of 53 selected anti-mycobacterial NPs against known ‘druggable’ mycobacterial targets ClpP1P2, DprE1, InhA, KasA, PanK, PknB and Pks13. The docking scores / binding free energies were predicted and calculated using AutoDock Vina along with physicochemical and structural properties of the NPs, using PaDEL descriptors. These were compared to the established inhibitor (control) drugs for each mycobacterial target. The specific interactions of the bisbenzylisoquinoline alkaloids 2-nortiliacorinine, tiliacorine and 13’-bromotiliacorinine against the targets PknB and DprE1 (-11.4, -10.9 and -9.8 kcal.mol-1 ; -12.7, -10.9 and -10.3 kcal.mol-1 , respectively) and the lignan αcubebin and Pks13 (-11.0 kcal.mol-1 ) had significantly superior docking scores compared to controls. Our approach can be used to suggest predicted targets for the NP to be validated experimentally but these in silico steps are likely to facilitate drug optimisation.

Sign in / Sign up

Export Citation Format

Share Document