Synthetic Silvestrol Analogues as Potent and Selective Protein Synthesis Inhibitors

Liu, Tao; Nair, Somarajan; Lescarbeau, André; Belani, Jitendra D.; Peluso, Stéphane; Conley, James; Tillotson, Bonnie; O’Hearn, Patrick J.; Smith, Sherri; Slocum, Kelly L.; West, Kip A.; Helble, Joseph; Douglas, Mark; Bahadoor, Adilah; Ali, Janid A.; McGovern, Karen; Fritz, Christian; Palombella, Vito J.; Wylie, Andrew; Castro, Alfredo; Tremblay, Martin

doi:10.1021/jm3011542

Cited by 67 publications

(101 citation statements)

References 50 publications

(136 reference statements)

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“…First, we prepared the Indonesian natural product compounds by searching the molecular structures through several journals and databases [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69], after which we were drawing them using ChemBioDraw 14.0 software. From this step, we obtained about 3429 compounds in the process.…”

Section: Our In Silico Methodsmentioning

confidence: 99%

Bioinformatics Approach to Screening and Developing Drug against Ebola

Tambunan¹,

Alkaff²,

Nasution³

2018

Advances in Ebola Control

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Ebola is an acute disease causing hemorrhagic fever marked with high mortality rate. The patients who suffer from Ebola only receive palliative care because there is no available drug which can consistently cure this disease. To date, no cure has been found to treat this disease. Bioinformatics and computer-aided drug discovery and development (CADDD) are employed to utilize the readily available genomic and proteomic data and enhance the hit rate of the novel and repurposed drug for Ebola therapy. Additionally, the time and cost of wet laboratory experiments can be drastically reduced by the support of bioinformatics approach. Our laboratory has succeeded not only in creating the bioinformatics research pipeline but also screening and developing the drug candidate to cure Ebola. Through pharmacophore-based virtual screening and molecular docking simulations, we discovered that about three Indonesian natural product compounds have noteworthy molecular interactions against EBOV VP35 protein, which are responsible for the RNA synthesis of the Ebola. These compounds can be reevaluated further through advances in in silico simulation and in vitro experiments.

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Section: Our In Silico Methodsmentioning

confidence: 99%

Bioinformatics Approach to Screening and Developing Drug against Ebola

Tambunan¹,

Alkaff²,

Nasution³

2018

Advances in Ebola Control

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“…In this study, all Indonesian natural product ligands were obtained from a various study that has been conducted previously, including from HerbalDB database [32,[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. These ligand structures were redrawn by using PerkinElmer ChemBioDraw Ultra 13.0, which can be saved later in .mol format.…”

Section: Acquiring the Indonesian Natural Product Ligands And Vp24 Prmentioning

confidence: 99%

Identification of novel Ebola virus (EBOV) VP24 inhibitor from Indonesian natural products through in silico drug design approach

Tambunan¹,

Nasution²

2017

AIP Conference Proceedings

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Sensitivity differences between microporous NaY and hierarchical ZSM-5 modified electrodes as ammonia gas sensor AIP Conference Proceedings 1862, 030081 (2017) Abstract. Ebola remains as one of the deadliest diseases in the world, with almost 29,000 cases were reported and kill 11,000 of them, and yet neither treatment nor vaccine that can combat this disease effectively. This disease is caused by ebolavirus (EBOV), a primary member of Filoviridae family. The life cycle of this virus has been operated by several key proteins, one of them is VP24 protein, which has been known for its crucial role in the transcription and replication of EBOV. Therefore, targeting VP24 protein can be a solution for treating this pathogenic disease. In this study, virtual screening of Indonesian natural products as EBOV VP24 inhibitor was performed. About 2,020 ligands from many sources, including HerbalDB database, were obtained and screened by using DataWarrior software to measure its molecular and pharmacological properties, resulting 301 ligands in the process. Then, the molecular docking simulation was performed to check the ligand's binding interaction and affinity with EBOV VP24 protein; this simulation was done by using MOE 2014.09 software. This study resulted that cycloartocarpin was the best ligand to inhibit the EBOV VP24 protein. Therefore, this ligand should be checked its stability through molecular dynamics simulation and performed in vitro test to verify its bioactivity against the EBOV VP24 protein.

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“…The inefficiency of oral delivery is thought to be attributed to the fact that silvestrol is a substrate for the multi-drug resistance 1 (MDR1) efflux pump [150]-a drug transporter present in the intestinal mucosa lining and which can prevent efficient drug absorption [151]. SAR studies have revealed that analogues lacking the dioxanyl moiety have a significant decreased affinity for MDR1 [152]. Some of these derivatives are comparable to silvestrol with respect to targeting eIF4A and extending tumor-free survival in preclinical mouse lymphoma models, while also having the added benefit of a simplified synthesis strategy [152,153].…”

Section: Rocaglatesmentioning

confidence: 99%

“…SAR studies have revealed that analogues lacking the dioxanyl moiety have a significant decreased affinity for MDR1 [152]. Some of these derivatives are comparable to silvestrol with respect to targeting eIF4A and extending tumor-free survival in preclinical mouse lymphoma models, while also having the added benefit of a simplified synthesis strategy [152,153].…”

Section: Rocaglatesmentioning

confidence: 99%