Discovering new mTOR inhibitors for cancer treatment through virtual screening methods and in vitro assays

Wang, Ling; Chen, Lei; Yu, Miao; Xu, Lihui; Cheng, Bao; Lin, Yongsheng; Gu, Qiong; He, Xian-Hui; Xu, Jing

doi:10.1038/srep18987

Cited by 39 publications

(25 citation statements)

References 43 publications

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“…Through the application of the ligand-based virtual screening (LBVS) technique on the PubChem database (https://pubchem.ncbi.nlm.nih.gov/) [17], we found molecules similar to NNPT and evaluated them through molecular docking, molecular dynamics (MD) simulations, and Molecular mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) calculations, in order to verify their behavior when bound to RTA. Similar computational methodologies have been applied before and proven to lead to promising experimental results [18][19][20][21]. We postulated that a ligand that is capable of simultaneously stablishing H-bonds with residues of the active site and of the secondary site of RTA is more likely to show satisfactory inhibitory activity than the current inhibitors that were already shown to occupy solely the active site [14][15][16].…”

Section: Introductionmentioning

confidence: 85%

Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors

Botelho

Santos

Gonçalves³

et al. 2020

Toxins

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Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.

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Section: Introductionmentioning

confidence: 85%

Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors

Botelho

Santos

Gonçalves³

et al. 2020

Toxins

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show abstract

“…A total of 57423 ligand molecules were obtained from the TCM database @Taiwan ( http://tcm.cmu.edu.tw ) [ 17 – 19 ] and refined as the following protocol. First, we did the pretreatment for each molecular structure, including removing the counterions, solvent moieties and salts, adding hydrogen atoms, and optimizing the structures based on the MMFF94 force field using MOE (version 2010.10, Chemical Computing Group, Inc., Canada) [ 20 – 23 ]. Second, the refined database was filtered using drug-like analysis including Lipinski rules of five and PAINS assay http://cbligand.org/PAINS ) [ 24 , 25 ].…”

Section: Methodsmentioning

confidence: 99%

Identification of Potent Chloride Intracellular Channel Protein 1 Inhibitors from Traditional Chinese Medicine through Structure-Based Virtual Screening and Molecular Dynamics Analysis

Wang

Wan

Liao

et al. 2017

BioMed Research International

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Chloride intracellular channel 1 (CLIC1) is involved in the development of most aggressive human tumors, including gastric, colon, lung, liver, and glioblastoma cancers. It has become an attractive new therapeutic target for several types of cancer. In this work, we aim to identify natural products as potent CLIC1 inhibitors from Traditional Chinese Medicine (TCM) database using structure-based virtual screening and molecular dynamics (MD) simulation. First, structure-based docking was employed to screen the refined TCM database and the top 500 TCM compounds were obtained and reranked by X-Score. Then, 30 potent hits were achieved from the top 500 TCM compounds using cluster and ligand-protein interaction analysis. Finally, MD simulation was employed to validate the stability of interactions between each hit and CLIC1 protein from docking simulation, and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) analysis was used to refine the virtual hits. Six TCM compounds with top MM-GBSA scores and ideal-binding models were confirmed as the final hits. Our study provides information about the interaction between TCM compounds and CLIC1 protein, which may be helpful for further experimental investigations. In addition, the top 6 natural products structural scaffolds could serve as building blocks in designing drug-like molecules for CLIC1 inhibition.

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“…The virtual screening method as previously reported [26,27]. Briefly, standard precision of Autodock Vina was employed to screen the tetrapeptide library.…”

Section: Peptide Library and Virtual Screeningmentioning

confidence: 99%

EGAR, A Food Protein-Derived Tetrapeptide, Reduces Seizure Activity in Pentylenetetrazole-Induced Epilepsy Models Through α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionate Receptors

Cai

Ling

et al. 2017

Neurotherapeutics

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A primary pathogeny of epilepsy is excessive activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs). To find potential molecules to inhibit AMPARs, high-throughput screening was performed in a library of tetrapeptides in silico. Computational results suggest that some tetrapeptides bind stably to the AMPAR. We aligned these sequences of tetrapeptide candidates with those from in vitro digestion of the trout skin protein. Among salmon-derived products, Glu-Gly-Ala-Arg (EGAR) showed a high biological affinity toward AMPAR when tested in silico. Accordingly, natural EGAR was hypothesized to have anticonvulsant activity, and in vitro experiments showed that EGAR selectively inhibited AMPAR-mediated synaptic transmission without affecting the electrophysiological properties of hippocampal pyramidal neurons. In addition, EGAR reduced neuronal spiking in an in vitro seizure model. Moreover, the ability of EGAR to reduce seizures was evaluated in a rodent epilepsy model. Briefer and less severe seizures versus controls were shown after mice were treated with EGAR. In conclusion, the promising experimental results suggest that EGAR inhibitor against AMPARs may be a target for antiepilepsy pharmaceuticals. Epilepsy is a common brain disorder characterized by the occurrence of recurring, unprovoked seizures. Twenty to 30 % of persons with epilepsy do not achieve adequate seizure control with any drug. Here we provide a possibility in which a natural and edible tetrapeptide, EGAR, can act as an antiepileptic agent. We have combined computation with in vitro experiments to show how EGAR modulates epilepsy. We also used an animal model of epilepsy to prove that EGAR can inhibit seizures in vivo. This study suggests EGAR as a potential pharmaceutical for the treatment of epilepsy.

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Discovering new mTOR inhibitors for cancer treatment through virtual screening methods and in vitro assays

Cited by 39 publications

References 43 publications

Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors

Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors

Identification of Potent Chloride Intracellular Channel Protein 1 Inhibitors from Traditional Chinese Medicine through Structure-Based Virtual Screening and Molecular Dynamics Analysis

EGAR, A Food Protein-Derived Tetrapeptide, Reduces Seizure Activity in Pentylenetetrazole-Induced Epilepsy Models Through α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionate Receptors

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